Physiology_Levy

Physiology_Levy. Mosby;2002.) at the nodes of Ranvier and are not found between them. Thus the action potential is regenerated only at the nodes of Ranvier (0.3-2 mm apart) rather than being regenerated continuously along the fiber, as is the case in an unmyelinated fiber. Resistance to the flow of ions across the many layers that make up the myelin sheath is so high that transmembrane currents are largely restricted to the short stretches of naked plasma membrane that are present at the nodes of Ranvier (see Fig. 5.10C ). Therefore, the action potential is regenerated at each successive node. The local currents entering the node are almost entirely conducted from one node to the next node, bringing each node to threshold in about 20 µsec. Thus the action potential appears to “jump” from one node of Ranvier to the next, and the process is called saltatory (from the Latin word saltare, “to leap”) conduction ( Fig. 5.11 Functional Consequences of Myelination


Physiology_Levy

Physiology_Levy. Fig. 5.11 Functional Consequences of Myelination The functional consequences of myelination can be highlighted by a comparison of squid and mammalian axons. Although human nerve fibers are much smaller in diameter than squid giant axons, human axons conduct at comparable or even faster speeds because of myelination. The unmyelinated squid giant axon has a 500-µm diameter and a conduction velocity of about 20 m/sec. In mammals, axon diameters range from about 0.2 to 20 µm, and all fibers with diameters larger than 1-2 µm are myelinated. An unmyelinated mammalian nerve fiber, which has a diameter of less than 1 to 2 µm, has a conduction velocity of less than 2 m/sec (see


Physiology_Levy

Physiology_Levy. Fig. 5.9 ), as expected because of its smaller diameter in comparison to the squid giant axon. In contrast, a 10-µm myelinated mammalian fiber has a conduction velocity in the range of 50 m/sec, more than twice that of the 500-µm squid giant axon, despite being 1/50 of its diameter. Thus the high conduction velocity with far narrower axons achieved by myelination allows a tremendous increase in neuronal connectivity without enormously expanding the volume of the CNS. This is certainly one factor that enabled the evolution of mammalian nervous systems with their huge numbers of neurons that are able to generate everything from fast reflexes to efficient and complex mental processing.


Physiology_Levy

Physiology_Levy. To receive information about the world, the CNS contains a wide variety of sensory receptors, each of which is specialized •Fig. 5.11 Comparison of Action Potential Conduction in an Unmyelinated Axon and in a Myelinated Axon. Attheinitialtime(A andC),anactionpotentialisbeinggeneratedattheleftsideofeachaxon.Notethattheinwardcurrentintheunmyelinatedaxon(A) isdepolarizinganadjacentportion,whereastheinwardcurrentinthemyelinatedaxon(C) isdepolarizingallofthemembranetothenextnode.Atthesecondinstantintime(B andD),theactionpotentialintheunmyelinatedaxon(B) hasbeengeneratedintheadjacentportion,whereastheactionpotentialinthemyelinatedaxon(D) hasbeengeneratedatsubsequentnodesandisalreadydepolarizingthelastnodetotheright.(RedrawnfromCastroA,etal:Neuroscience: An Outline Approach. Philadelphia:Mosby;2002.)


Physiology_Levy

Physiology_Levy. Insomediseasesknownasdemyelinating disorders, themyelinsheathdeteriorates.Inmultiple sclerosis, scatteredprogressivedemyelinationofaxonsintheCNSresultsinlossofmotorcontrolandsensorydeficits.Theneuropathycommoninseverecasesofdiabetesmellitusiscausedbythedemyelinationofperipheralaxons.Whenmyelinislost,thelengthconstantbecomesmuchshorter.Hence,theactionpotentiallosesamplitudeasitiselectrotonicallyconductedfromonenodeofRanviertothenext.Ifdemyelinationissufficientlysevere,theactionpotentialmayarriveatthenextnodeofRanvierwithinsufficientstrengthtofireanactionpotentialatthatnode,leadingtopropagationfailure. to detect a particular type of energy (stimulus). When a stimulus activates a sensory receptor, it initiates a process called sensory transduction by which information about the stimulus (e.g., its intensity and duration) is converted into local electrical signals. These local signals are called


Physiology_Levy


Physiology_Levy

Physiology_Levy. action potential.Theclinicalvalueofsucharecordingisitsability,incertaindiseasestates,torevealthedysfunctionofaparticulargroupofaxonsassociatedwithspecificfunctions,aswellasthenoninvasivenatureofthetechniquebecauseitcanbeperformedwithskinsurfaceelectrodes( receptor or generator potentials. The receptor potentials can then be transformed into patterns of action potentials that are conducted over one or more axons into the CNS. In order for this to happen, the stimulus must produce receptor potentials that are large enough to change the spiking levels of one or more primary afferent fibers that are connected to the receptor. Weaker intensities of stimulation can produce subthreshold receptor potentials, but such stimuli do not change the activity of central sensory neurons and thus are not detected. Thus stimulus threshold is defined as the weakest stimulus that can be reliably detected.


Physiology_Levy

Physiology_Levy. Environmental events that evoke sensory transduction can be mechanical, thermal, chemical, or other forms of energy. However, the types of information used by a CHAPTER 5 Generation and Conduction of Action Potentials particular organism depend on its set of sensory receptors. For example, humans cannot sense electrical or magnetic fields, but other animals can sense such stimuli. In particular, many fish have electroreceptors, and various fish and birds use the earth’s magnetic field to orient themselves during migration. The transduction process varies with the type of environmental stimulus being detected. Fig. 5.13 shows three examples of how stimuli can alter the membrane properties of the specific sensory receptors that transduce such stimuli 0246 (further details for each of these examples are given in other 36 72 108 m/s chapters).


Physiology_Levy

Physiology_Levy. Fig. 5.13A illustrates how a chemoreceptor, such A as that used for taste and smell, might respond when a chemical stimulant reacts with receptor molecules on the plasma membrane of the sensory receptor. Binding of the •Fig. 5.12 Thedistributionofaxons,bysizeandconductionvelocity,inamixed(muscle)nerve(A) andacutaneousnerve(B). Notetheincreasednumberofsmall-diameterfibersandtheabsenceofAα fibersinthecutaneousnerve.(FromHainesDE[ed].Fundamental Neuroscience for Basic and Clinical Applications. 3rded.Philadelphia:ChurchillLivingstone;2006.) chemical stimulant to the receptor molecule opens an ion channel, which enables the influx of an ionic current that depolarizes the sensory receptor cell. (This is similar to what is described for ligand-gated channels in Chapter 6.)


Physiology_Levy

Physiology_Levy. Chapter 6.) Fig. 5.13B, the ion channel of a mechanoreceptor, such as those in the skin, opens in response to the application of a mechanical force along the membrane, and this allows an influx of current to depolarize the sensory receptor. In Fig. 5.13C, the ion channel of a retinal photoreceptor cell (so-called because it responds to light) is open in the dark and closed when a photon is absorbed by pigment on an internal disc membrane. In this case, an influx of current occurs in the dark; the current ceases when light is applied. When the current stops, the photoreceptor hyperpolarizes. (Because capture of the photon is distant from the ion channel that it influences, this process must involve an intracellular “second messenger” mechanism.) The nature of the receptor also can vary. In the simplest situation, a receptor is just a specialized portion of an axon,


Physiology_Levy

Physiology_Levy. The nature of the receptor also can vary. In the simplest situation, a receptor is just a specialized portion of an axon, Aα N/A8-1344-78ExtrafusalskeletalmusclefibersAγ N/A2-812-48IntrafusalmusclefibersBN/A1-36-18PreganglionicautonomicfibersCN/A0.2-20.5-2Postganglionicautonomicfibers FromHainesDE(ed).Fundamental Neuroscience for Basic and Clinical Applications. 3rded.Philadelphia:ChurchillLivingstone;2006.N/A,notapplicable. •Fig. 5.13 Models of Transducer Mechanisms in Three Types of Receptors. A, Chemoreceptor.B, Mechanoreceptor.C, Photoreceptor. in which case the transduction of a stimulus into receptor potential and the translation of this potential into a spike train all take place in the same cell. For example, a mechanical stimulus, such as pressure on the skin of a finger, can distort the membrane of an axon that forms part of a mechanoreceptor, as shown in


Physiology_Levy

Physiology_Levy. Fig. 5.14A . This distortion causes inward current flow at the end of the axon and longitudinal and outward current flow along the neighboring parts of the axon. The outward current produces a depolarization (the receptor potential) that might exceed the threshold for an action potential (see Fig. 5.14B ). If so, one or more action potentials are evoked and then travel along this primary afferent fiber to the CNS and thereby convey information about the mechanical stimulus. In many other cases, the receptor is composed of more than one cell. In this situation, transduction occurs in one cell, but spikes are generated in other cells that are •Fig. 5.14 A, Currentflow(thin arrows) producedbystimulation(thick arrow) ofamechanoreceptoratthetipofanaxon.AnintracellularrecordingelectrodeisplacedatthefirstnodeofRanvier.B, ThereceptorpotentialproducedbythecurrentandanactionpotentialthatwouldbesuperimposedonthereceptorpotentialifitweretoexceedthresholdatthefirstnodeofRanvier.


Physiology_Levy

Physiology_Levy. synaptically connected to it (see ). For example, in the cochlea, the primary afferent fibers get synaptic input from mechanoreceptive hair cells. Sensory transduction in such sense organs can be more complex in this arrangement. In photoreceptors, moreover, the receptor potential is hyperpolarizing, as mentioned earlier, and interruption of the dark current is the signal event. Information about each of these mechanisms is discussed in Chapter 8. Although the mechanisms of sensory transduction vary between stimulus types, the end result is typically a receptor potential in either the receptor cell or the primary afferent neuron (i.e., the first neuron in a sensory pathway) that has a synapse with the receptor cell.


Physiology_Levy

Physiology_Levy. The relationship between the location of a stimulus and activation of particular sensory neurons is a major theme in the field of sensory physiology. The receptive field of a sensory neuron is the region that, when stimulated, affects the activity of that neuron. For example, a sensory receptor might be activated by indentation of only a small area of skin. That area is the excitatory receptive field of the sensory receptor. Moreover, a neuron in the CNS might have a receptive field several times as large as that of a sensory receptor because it may receive information from many sensory receptors, each with a slightly different receptive field. The receptive field of that CNS neuron is thus the sum of the receptive fields of the sensory receptors that influence it. The location of the receptive field is determined by the location of the sensory transduction apparatus responsible for signaling information about the stimulus to the sensory neuron.


Physiology_Levy

Physiology_Levy. In general, sensory receptive fields are excitatory. However, a central sensory neuron can have either an excitatory or an inhibitory receptive field or, indeed, a complex receptive field that includes areas that excite it and areas that inhibit it. Examples of such complex receptive fields are discussed in Coding of Information by Action Potentials


Physiology_Levy

Physiology_Levy. Coding of Information by Action Potentials Central to CNS function is the transmission of information between neurons. This is accomplished primarily through action potentials, which propagate down the axon to the presynaptic terminals and cause neurotransmitter release, signaling the postsynaptic cells. As already explained, the regenerative nature of action potentials allows them to carry signals regardless of the length of the axon, whereas local signals, such as receptor or synaptic potentials (see ), decay with distance and are therefore not suitable for this purpose. The tradeoff, however, is that the all-or-none nature of action potentials means that their shape and size do not generally convey information in the way gradations of local potentials do. Instead, the variations in the rate or timing of action potentials appear to be used primarily as the “codes” for transmission of information between neurons.


Physiology_Levy

Physiology_Levy. Rate coding refers to information being coded in the firing rate of a neuron, where firing rate is defined as the number of spikes fired per unit time, usually expressed as spikes/second, also called hertz (Hz). For example, the force of a mechanical stimulus to the skin can be encoded in the firing rate of the primary afferent neuron that innervates the skin; the greater the force applied to the skin, the larger the resulting receptor potential in the primary afferent neuron will be and, as a consequence, the faster the rate of action potentials triggered by the receptor potential will be. Research has shown many neurons employ rate coding in the sense that the firing rate of a neuron shows a consistent relationship to particular parameters of sensory stimuli, upcoming movements, or other aspects of behavior.


Physiology_Levy

Physiology_Levy. The amount of information in such rate codes is constrained by several factors. One factor is a neuron’s range of firing rates. The upper limit of this range is set by the maximal frequency that a neuron can fire action potentials, which is determined by the duration of the absolute and relative refractory periods (see Fig. 5.4 ) and rarely exceeds 1000 Hz. The lower limit of the firing range is, of course, 0 Hz, as neurons cannot fire at negative rates. To avoid this problem, many neurons have spontaneous activity levels. These can be quite high (e.g., some Purkinje cells fire spontaneously at 100 Hz) and let a cell either increase or decrease its activity over a similar range in response to inputs. A second constraining factor is the variability of neuron’s firing rate, which determines the resolution of the neuron’s information coding. CHAPTER 5 Generation and Conduction of Action Potentials


Physiology_Levy

Physiology_Levy. CHAPTER 5 Generation and Conduction of Action Potentials Timing, or temporal coding, refers to spike codes in which the specific timing of spikes rather than the overall firing rate encodes information. One often-studied version of temporal coding is the synchronization of spikes across neurons. Synchronization of neuronal spiking has been shown to occur in a number of brain regions and has been related to function in a number of instances. An advantage of temporal coding is that it can convey information more quickly than can rate coding, inasmuch as it does not require averaging, which takes time. Moreover, rate coding and temporal coding are not mutually exclusive, inasmuch as overall firing rates can be varied while synchronous events are superimposed. Such multiplexing of codes may increase the information transmission capacity of neuronal pathways.


Physiology_Levy

Physiology_Levy. Sensory neurons encode information about stimuli. In the process of sensory transduction, one or more aspects of the stimulus must be encoded in a way that can be interpreted by the CNS. The encoded information is an abstraction based on (1) which sensory receptors are activated, (2) the responses of sensory receptors to the stimulus, and (3) information processing in the sensory pathway. Some stimulus parameters that can be encoded include sensory modality, location, intensity, frequency, and duration. Other aspects of stimuli that are encoded are described in relation to particular sensory systems in later chapters.


Physiology_Levy

Physiology_Levy. A sensory modality is a class of sensation. For example, sustained mechanical stimuli applied to the skin result in sensations of touch or pressure, and transient mechanical stimuli may evoke sensations of flutter or vibration. Other cutaneous modalities include cold, warmth, and pain. Vision, audition, taste, and smell are examples of noncutaneous sensory modalities. The specific sensory receptors define the normal energy associated with the modality of a sensory pathway. For example, the visual pathway includes photoreceptors, neurons in the retina, the lateral geniculate nucleus of the thalamus, and the visual areas of the cerebral cortex (see ). The normal means of activating the visual pathway is light striking the retina. However, mechanical stimulation (e.g., pressure on the eyeball) or electrical stimulation of neurons in the visual pathway also produce a visual sensation. Thus neurons of the visual system can be regarded as a labeled line, which, when activated by whatever


Physiology_Levy

Physiology_Levy. or electrical stimulation of neurons in the visual pathway also produce a visual sensation. Thus neurons of the visual system can be regarded as a labeled line, which, when activated by whatever means, results in a visual sensation.


Physiology_Levy

Physiology_Levy. The location of a stimulus is signaled by activation of the particular population of sensory neurons whose receptive fields are affected by the stimulus. The information may be encoded in the CNS as a neural map. For example, a somatotopic map is formed by arrays of neurons in the somatosensory cortex that receive information from corresponding locations on the body surface (see ). In the visual system, points on the retina are represented by neuronal arrays that form retinotopic maps (see


Physiology_Levy

Physiology_Levy. Intensity may be encoded in a number of ways. Because action potentials have a uniform magnitude, some sensory neurons encode intensity by their frequency of discharge (rate coding). The relationship between stimulus intensity and response can be plotted as a stimulus-response function. For many sensory neurons, the stimulus-response function approximates an exponential curve with an exponent that can be less than, equal to, or greater than 1. Stimulus-response functions with fractional exponents characterize many mechanoreceptors. Thermoreceptors, which detect changes in temperature, have linear stimulus-response curves (exponent of 1). Nociceptors, which detect painful stimuli, may have linear or positively accelerating stimulus-response functions (i.e., the exponent for these curves is 1 or greater). The positively accelerating stimulus-response functions of nociceptors help explain the urgency that is experienced as the pain sensation increases.


Physiology_Levy

Physiology_Levy. Another way in which stimulus intensity is encoded is according to the number of sensory receptors that are activated. A stimulus at the threshold for perception may activate only one or only a few primary afferent neurons of an appropriate class, whereas a strong stimulus of the same type may recruit many similar receptors. Central sensory neurons that receive input from sensory receptors of this particular class would be more powerfully affected as more primary afferent neurons discharge. Greater activity in central sensory neurons may be perceived as a stronger stimulus.


Physiology_Levy

Physiology_Levy. Stimuli of different intensities may also activate different sets of sensory receptors. The limit of a neuron’s firing rate of action potentials can also limit its range of response to a stimulus. However, mechanoreceptors with different thresholds can overcome this problem: Those with low thresholds can signal over a range of low input intensities, whereas others with higher thresholds can signal higher input intensities. Together they allow fine resolution over an extended range of intensities. In addition, still higher intensities might recruit nociceptors, and that will also change the perceived quality of the stimulus.


Physiology_Levy

Physiology_Levy. Stimulus frequency can sometimes be encoded by action potentials whose interspike intervals correspond exactly to the intervals between stimuli (e.g., at intervals corresponding •Fig. 5.15 Responses of Slowly and Rapidly Adapting Mechanoreceptors to Displacement of the Skin. A toC arethedischargesofprimaryafferentfibersduringaramp-and-holdstimulusshowninD. A, Theresponseofaslowlyadaptingreceptorthatsignalsthemagnitudeanddurationofdisplacement.B, Theresponseofarapidlyadaptingreceptorwhoseoutputsignalsthevelocityofdisplacement.C, Theresponseofadifferentrapidlyadaptingreceptorthatrespondstoacceleration.p,displacement;R,response;t,time.


Physiology_Levy

Physiology_Levy. to that of a low-frequency vibration). However, this mechanism is limited by the firing rate limits of neurons as discussed earlier. When higher frequencies need to be encoded (e.g., the auditory system, which in humans is capable of detecting frequencies up to 20,000 Hz; see ), other strategies are needed. Other candidate codes depend on the spatiotemporal patterns of firing across populations of neurons. The duration and the onset and offset of events are encoded by different populations of sensory neurons. For example, slowly adapting receptors in the skin produce a repetitive discharge throughout a prolonged stimulus. However, rapidly adapting receptors produce spikes at the onset (or offset) of the same stimulus.


Physiology_Levy

Physiology_Levy. Fig. 5.15 shows the responses of three types of receptors to the slow deflection of the skin, which is depicted in the graph at the bottom of the figure. The functional implication is that different temporal features of a stimulus can be signaled by receptors with different adaptation rates. 1. Ion channels are integral membrane proteins that have ion-selective pores. An ion channel typically has two states: high conductance (open) and zero conductance (closed). Different regions of an ion channel protein act as gates to open and close the channel. The channel flips spontaneously between the open and closed states. 2. For a voltage-dependent channel, the fraction of time that the channel spends in the open state is a function of the transmembrane potential difference. 3. The action potential is generated by the rapid opening and subsequent voltage inactivation of voltage-dependent Na+ channels and by the delayed opening and closing of voltage-dependent K+ channels. 4.


Physiology_Levy

Physiology_Levy. 4. The absolute and relative refractory periods result from voltage inactivation of Na+ channels and the delayed closure of K+ channels in response to membrane repolarization. These refractory periods limit the firing rate of action potentials. 5. Subthreshold signals and action potentials are conducted along the length of a cell by local circuit currents. Subthreshold signals are conducted only electrotonically, and thus decrease with distance. 6. The action potential is propagated rather than merely conducted; it is regenerated as it moves along the axon. In this way, an action potential retains the same size and shape as it travels along the axon. 7. A large-diameter axon has greater propagation velocity because increased axon diameter lowers axial resistance and allows greater amounts of current to flow farther down the axon. 8.


Physiology_Levy

Physiology_Levy. 7. A large-diameter axon has greater propagation velocity because increased axon diameter lowers axial resistance and allows greater amounts of current to flow farther down the axon. 8. Myelination dramatically increases the conduction velocity of a nerve axon because myelin increases membrane resistance and lowers membrane capacitance. Myelination allows an action potential to Fain GL. Molecular and Cellular Physiology of Neurons. 2nd ed. Cambridge, MA: Harvard University Press; 2014. Hille B. Ion Channels of Excitable Membranes. 3rd ed. Sunderland, MA: Sinauer Associates; 2001. Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952;117:500-544. CHAPTER 5 Generation and Conduction of Action Potentials be conducted very rapidly from one node of Ranvier to the next. This makes the action potential appear to jump from node to node in a form of conduction called saltatory conduction. 9.


Physiology_Levy

Physiology_Levy. 9. A receptor responds preferentially to a particular form of stimulus energy. Its receptive field is that part of a sensory domain in which energy can affect the receptor. 10. Receptor potentials are the result of transduction of sensory stimuli. These potentials reflect the specific parameters of the stimulus and, if they exceed threshold, alter the action potential firing patterns of the afferent neurons. Johnston D, Wu SM-S. Foundations of Cellular Neurophysiology. Cambridge, MA: MIT Press; 1994. Sakmann B, Neher E. Single-Channel Recording. 2nd ed. Philadelphia: Springer; 1995. Upon completion of this chapter the student should be able to answer the following questions: 1. What are the characteristics of electrical synapses? 2. What are the specializations found in the presynaptic and postsynaptic elements of a chemical synapse? 3. What sequence of events connect the arrival of the action potential at the presynaptic terminal to the entry of calcium? 4.


Physiology_Levy

Physiology_Levy. 3. What sequence of events connect the arrival of the action potential at the presynaptic terminal to the entry of calcium? 4. What sequence of events connect the entry of calcium at the presynaptic terminal to release of neurotransmitter? 5. What is the quantal hypothesis of synaptic transmission, and how does the presence of miniature end plate potentials support this hypothesis? 6. Why is the reversal potential of a typical EPSP near 0 mV? 7. What distinguishes EPSPs and IPSPs in terms of underlying ionic conductances, effect on membrane potential, and neuronal firing probability? 8. How does an IPSP still inhibit a neuron when its reversal potential is equal to or more positive than the neuron’s resting potential? 9. What are the mechanisms by which synaptic effects can change over time? 10. What are the criteria for determining a substance is a neurotransmitter, and what are the major excitatory and inhibitory neurotransmitters? 11.


Physiology_Levy

Physiology_Levy. 10. What are the criteria for determining a substance is a neurotransmitter, and what are the major excitatory and inhibitory neurotransmitters? 11. What are the major classes of neurotransmitter receptors?


Physiology_Levy

Physiology_Levy. ynaptic transmission is the major process by which electrical signals are transferred between cells within the nervous system (or between neurons and muscle cells or sensory receptors). Within the nervous system, synaptic transmission is usually conceived of as an interaction between two neurons that occurs in a point-to-point manner at specialized junctions called synapses. Two main classes of synapses are distinguished: electrical and chemical. However, as the list of chemical neurotransmitters has grown and as understanding of their mechanisms of action has increased, the definition and conception of what constitutes synaptic transmission has had to be refined and expanded. We no longer think of synaptic transmission as a process that involves only neurons, but now realize that glia form an important element of the synapse and that signaling occurs between neurons and glia. Moreover, in some cases, neurotransmitter released at a synapse will act over a widespread territory rather


Physiology_Levy

Physiology_Levy. an important element of the synapse and that signaling occurs between neurons and glia. Moreover, in some cases, neurotransmitter released at a synapse will act over a widespread territory rather than just at the synapse from which it is released. Thus, we must either generalize the definition of synaptic transmission or consider classically defined synaptic transmission as but one of several mechanisms by which cells in the nervous system communicate with each other. In this chapter we first describe the classic conception of synaptic transmission (electrical and chemical) and then introduce some of the nontraditional neurotransmitters and discuss how they have forced modifications in our conception of chemical communication between cells in the nervous system.


Physiology_Levy

Physiology_Levy. Although their existence in the mammalian central nervous system (CNS) has been known for a long time, electrical synapses, or gap junctions, between neurons were thought to be of relatively little importance for the functioning of the adult mammalian CNS. Only recently has it become apparent that these synapses are quite common and that they may underlie important neuronal functions. An electrical synapse is effectively a low-resistance pathway between cells that allows current to flow directly from one cell to another and, more generally, allows the exchange of small molecules between cells. Electrical synapses are present in the CNS of animals from invertebrates to mammals. They are present between glial cells as well as between neurons. Electrical coupling of neurons has been demonstrated for most brain regions, including the inferior olive, cerebellum, spinal cord, neocortex, thalamus, hippocampus, olfactory bulb, retina, and striatum.


Physiology_Levy

Physiology_Levy. A gap junction is the morphological correlate of an electrical synapse (see also ). These junctions are plaque-like structures in which the plasma membranes of the coupled cells become closely apposed (the intercellular space narrows to ≈ 3 nm) and filled with electron-dense material (Fig. 6.1 ). Freeze-fracture electron micrographs of gap junctions display regular arrays of intramembrane particles that correspond to proteins that form the intercellular channels connecting the cells. The typical channel diameter is large (1 to 2 nm), thus making it permeable not only to ions but also other small molecules up to approximately 1 kDa in size.


Physiology_Levy

Physiology_Levy. .28 µm • Fig. 6.1 Gap junction structure. A, Schematic view of the gap junction showing narrowing of the intercellularspaceto3.5nmatthejunction.Thegapjunctionhasmultiplechannels,witheachchannel formed by two connexon hemichannels. Each connexon in turn comprises six connexin subunits. B,Electronmicrographofpartofacomplexsynapticarrangementcalledaglomerulusthatisfoundin theinferioroliveandsomeotherCNSregions.Twodendriticspinesarecoupledbyagapjunction(small black arrows).Anaxonterminalpackedwithsynapticvesiclesfillstheupperrightpartofthepanel.Large arrowheadspointtotheelectron-densematerialthatmarkstheactivezones.Blackdotsareimmunogold labelingforGABA,thusidentifyingthisterminalasGABAergic.Redarrowheadspointtosynapticvesicles. (FromDeZeeuwCIetal.J Neurosci1996;16:3420.Copyright1996bytheSocietyforNeuroscience.)


Physiology_Levy


Physiology_Levy

Physiology_Levy. Electrical synapses are fast (essentially no synaptic delay) and bidirectional (i.e., current generated in either cell can flow across the gap junction to influence the other cell). In addition they act as low-pass filters. That is, slow electrical events are much more readily transmitted than are fast signals such as action potentials. One important role for neuronal gap junctions appears to be synchronization of network activity. For example, the activity of inferior olivary neurons is normally synchronized but becomes uncorrelated when pharmacological blockers of gap junctions are injected into the inferior olive. It also appears that the patterns of electrical coupling by gap junctions may be highly specific. For example, neocortical interneurons almost exclusively couple to interneurons of the same type. This specific gap junction–coupling pattern suggests that multiple, independent, electrically coupled networks of interneurons may coexist across the neocortex.


Physiology_Levy

Physiology_Levy. Finally, although electrical synapses are generally regarded as relatively simple and static in comparison to chemical synapses, they may actually be fairly dynamic entities. For example, the properties of electrical synapses can be modulated by several factors, including voltage, intracellular pH, and [Ca++]. Moreover, they are subject to regulation by G protein–coupled receptors, and connexins (the protein subunits that form a gap junction, see At The Cellular ) contain sites for phosphorylation. These factors can change the coupling between cells by causing changes in single-channel conductance, formation of new gap junctions, or removal of existing ones.


Physiology_Levy

Physiology_Levy. Chemical synaptic transmission was first demonstrated between the vagus nerve and the heart by a simple experiment by Otto Loewi. The vagus nerve of a frog was stimulated to slow the heart rate down while the solution perfusing the heart was collected. This solution was then used to perfuse a second heart, whose beating then also slowed, demonstrating that the vagal nerve stimulation had caused a chemical to be released into the solution. The chemical responsible was found to be acetylcholine, which we now know is also a neurotransmitter at the neuromuscular junction and at other synapses in the peripheral and central nervous systems.


Physiology_Levy

Physiology_Levy. Unlike the situation at electrical synapses, at chemical synapses there is no direct communication between the cytoplasm of the two cells. Instead the cell membranes are separated by a synaptic cleft of some 20 nm, and interaction between the cells occurs via chemical intermediaries known as neurotransmitters. Chemical synapses are generally unidirectional, and thus one can refer to the presynaptic and postsynaptic elements that are diagramed in Fig. 6.2. The presynaptic element is often the terminal portion of an axon and is packed with small vesicles whose exact shape and size vary with the neurotransmitter they contain. In addition, the presynaptic membrane apposed to the postsynaptic element has regions, known as active zones, of electron-dense material that corresponds to the proteins involved in transmitter release (see


Physiology_Levy

Physiology_Levy. Fig. 6.1B). Moreover, mitochondria and rough endoplasmic reticulum are typically found in the presynaptic terminal. The postsynaptic membrane is also characterized by electron-dense material, which in this case corresponds to the receptors for the neurotransmitter.


Physiology_Levy

Physiology_Levy. Chemical synapses occur between different parts of neurons. Traditionally, focus has been placed on synapses formed by an axon onto the dendrites or soma of a second cell (axodendritic or axosomatic synapses), and our description will be based primarily on such synapses. However, there are many additional types of chemical synapses, such as axoaxonic (axon to axon), dendrodendritic (dendrite to dendrite), and dendrosomatic (dendrite to soma). Furthermore, complex synaptic arrangements are possible, such as mixed synapses, in which cells form both electrical and chemical synapses with each other; serial synapses, in which an axoaxonic synapse is made onto the axon terminal and influences the efficacy of that terminal’s synapse with yet a third element; and reciprocal synapses, in which both cells can release transmitter to influence the other.


Physiology_Levy

Physiology_Levy. Fig. 6.1B shows a complex synaptic arrangement called a glomerulus that involves both chemical and electrical synapses among the participating elements. Much of what we know about chemical synapses comes from the study of two classic preparations, the frog neuromuscular junction (the synapse from a motor neuron onto a muscle fiber) and the squid giant synapse (the synapse from a second-order neuron onto third-order neurons that innervate the muscle of the squid’s mantle; i.e., the motor neurons whose axons were used to characterize the conductances underlying the action potential [see ]). The principles governing transmission at these synapses mostly apply to synapses within the mammalian CNS as well, at least with regard to synapses using what are called the “classic” neurotransmitters (see the section mitters). Thus, much of the following discussion will be based on results from these two preparations; however, some differences in CNS synapses will also be pointed out.


Physiology_Levy

Physiology_Levy. 3 Gaseous transmitters Arginine NO synthase Citrulline Mitochondria Peptides diffuse in extracellular space and bind to synaptic and extrasynaptic G protein–complex receptors Gaseous transmitters diffuse out of cell of origin and directly into other cells. They can act inside cell of origin or in cells distant from point of release G protein– coupled receptors NO Activates variety of enzymes Ionotropic and G protein– coupled receptors Acetyl CoA + Choline Reuptake by transporter 1 Small-molecule neurotransmitters AChAcetyl cholinesterase Other small-molecule neurotransmittersSmall-molecule neurotransmitters diffuse across synaptic cleft and bind to postsynaptic receptors Vesicle transporter concentrates neurotransmitter into vesicles Postsynaptic cell Presynaptic terminal Ca++ channels Large electron-dense vesicles NO O2 Nitrogen oxide (inactive) 2 Neuropeptides •Fig. 6.2


Physiology_Levy

Physiology_Levy. transporter concentrates neurotransmitter into vesicles Postsynaptic cell Presynaptic terminal Ca++ channels Large electron-dense vesicles NO O2 Nitrogen oxide (inactive) 2 Neuropeptides •Fig. 6.2 Schematicofachemicalsynapticterminalreleasingallthreemainclassesofneurotransmitter.Foreach,themechanismsofrelease,sitesofaction,andmechanismsforterminationofactivityareshown.Realsynapsesreleasetransmitterfromoneormoreclasses.


Physiology_Levy

Physiology_Levy. Synaptic transmission at a chemical synapse may be summarized as follows. Synaptic transmission is initiated by arrival of the action potential at the presynaptic terminal. The action potential depolarizes the terminal, which causes Ca++ channels to open. The subsequent rise in [Ca++] within the terminal triggers the fusion of vesicles containing neurotransmitter with the plasma membrane. The transmitter is then expelled into the synaptic cleft, diffuses across it, and binds to specific receptors on the postsynaptic membrane. Binding of transmitter to receptors then causes the opening (or less often, the closing) of ion channels in the postsynaptic membrane, which in turn results in changes in the potential and resistance of the postsynaptic membrane that alter the excitability of the cell. The changes in membrane potential of the postsynaptic cell are termed excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) (


Physiology_Levy

Physiology_Levy. Fig. 6.3 ), depending on whether they increase or decrease, respectively, the cell’s excitability, which can be defined as its probability of firing action potentials. The transmitter acts for only a very short time (milliseconds) because reuptake and degradation mechanisms rapidly clear the transmitter from the synaptic cleft.


Physiology_Levy

Physiology_Levy. The succeeding sections will amplify specific points of this summary. However, it is worth mentioning at this point that some of the nonclassic types of neurotransmitters (e.g., neuropeptides and gaseous neurotransmitters such as nitric oxide) and the discovery of metabotropic receptors have required modifications of several aspects of this basic conception. (Whereas an ionotropic receptor usually contains the ion channel as an integral part of itself, a metabotropic receptor does not contain an ion channel but instead is coupled to a G protein that initiates second messenger cascades that can ultimately affect ion channels.) Some of the differences between classic and peptide transmitters are listed in Table 6.1 . More details on the properties of peptide and gaseous transmitters are provided in the relevant parts of the section of this chapter, and metabotropic receptors are covered in the Receptors section. Calcium Entry Is the Signal for Transmitter Release


Physiology_Levy

Physiology_Levy. Depolarization of the presynaptic membrane by the action potential causes voltage-gated Ca++ channels to open, which makes it possible for Ca++ to flow into the terminal and trigger the release of transmitter. However, Ca++ will enter the terminal only if there is a favorable electrochemical gradient to do so. Recall that it is the combination of the concentration and voltage gradients that determines the direction of ion flow through open channels. Extracellular [Ca++] is high relative to intracellular [Ca++], which favors entry into the terminal; however, during the peak of the action potential, the membrane potential is positive, and the voltage gradient opposes the entry of Ca++ because of its positive charge. Thus, at the peak of the action potential, relatively little Ca++ enters the terminal because although the membrane is highly permeable to Ca++ , the overall driving force is small. In fact, by using a voltage clamp, one can experimentally make the membrane potential


Physiology_Levy

Physiology_Levy. the terminal because although the membrane is highly permeable to Ca++ , the overall driving force is small. In fact, by using a voltage clamp, one can experimentally make the membrane potential positive and equal to the Nernst equilibrium potential for Ca++ . If this is done, no Ca++ will enter the terminal despite Ca++ channels being open, and as a result no transmitter is released and no postsynaptic response is observed. This voltage is known as the suppression potential. If the membrane potential is rapidly made negative again (because of either the end of the action potential or by adjusting the voltage clamp), Ca++ rushes into the terminal as a result of the large driving force (which arises instantaneously on repolarization) and the high membrane permeability to Ca++ (which remains high because it takes the Ca++ channels several milliseconds to close in response to the new membrane potential), thereby resulting in release of transmitter and a postsynaptic response (


Physiology_Levy

Physiology_Levy. Fig. 6.4 •Fig. 6.3 IPSPsandEPSPsrecordedwithamicroelectrodeinacatspinalmotorneuroninresponsetostimulationofappropriateperipheralafferentfibers.Fortytracesaresuperimposed.NotethattheseIPSPsarehyperpolarizing,butinsomecasesIPSPscanbedepolarizing—seetextforanexplanation.(RedrawnfromCurtisDR,EcclesJC.J Physiol 1959;145:529.) Synaptic Vesicles and the Quantal Nature of Transmitter Release How neurotransmitter is stored and how it is released are questions fundamental to synaptic transmission. Answering these questions began with two observations. The first was the discovery of small round or irregularly shaped organelles known as synaptic vesicles in presynaptic terminals by electron microscopy (see


Physiology_Levy

Physiology_Levy. Figs. 6.1B 6.2 ). The second observation came from recordings of postsynaptic responses at the neuromuscular junction. Normally an action potential in a motor neuron causes a large depolarization in the postsynaptic muscle, termed an end plate potential (EPP), which is equivalent to an EPSP in a neuron. However, under conditions of low extracellular [Ca++], the EPP amplitude is reduced (because the presynaptic Ca++ current is reduced, leading to a smaller rise in intracellular [Ca++], and transmitter release is proportional to [Ca++]). In this condition, the EPP is seen to fluctuate among discrete values (


Physiology_Levy

Physiology_Levy. Fig. 6.5 ). Moreover, small spontaneous depolarizations of the postsynaptic membrane, termed miniature end plate potentials (mEPPs), are observable. The amplitude of the mEPP (≤1 mV) corresponds to that of the smallest EPP evoked under low [Ca++], and the amplitudes of other EPPs were shown to be integral multiples of the mEPP amplitude; thus, it was proposed that each mEPP corresponded


Physiology_Levy


Physiology_Levy

Physiology_Levy. andK+ conductancetoisolatetheCa++ conductance.)Electrode3recordsthemembranepotentialofthepostsynapticaxon.Thepresynapticterminalwasvoltage-clampedtoincreasinglymoredepolarizedlevels(blue traces). Withasmalldepolarization(B), asmallCa++ currentstartsshortlyafterthevoltagestep,continuestogrowforthedurationofthestep(oncurrent),andthendecaysexponentiallyafteritstermination(offortailcurrent).Alargervoltagestep(C) increasesboththeonandtheoffcomponentsoftheCa++ current,andnowdistinctonandoffresponsesareobservedinthepostsynapticresponse.D, ThevoltagestepistotheNernstpotentialforCa++ ,sothereisnoCa++ currentduringthestep,butalargetailcurrentandoffresponseareobserved.(BasedondataofLlinasRetal.Biophys J 1981;33:323.) to the release of transmitter from a single vesicle and that EPPs represented the combined simultaneous release of transmitter from many vesicles.


Physiology_Levy

Physiology_Levy. This linking of mEPPs and vesicles implies that each mEPP is caused by the action of many molecules of neurotransmitter binding to postsynaptic receptors. The alternative that each mEPP could be caused by a single transmitter molecule binding to and opening a single postsynaptic receptor was rejected, in part because responses smaller in amplitude than mEPPs could be generated experimentally by directly applying dilute solutions of acetylcholine to the muscle. In fact, mEPPs were calculated to be caused by the action of approximately 10,000 molecules, which corresponds well to estimates of the number of neurotransmitter molecules contained within a single vesicle.


Physiology_Levy

Physiology_Levy. Many additional studies have confirmed the vesicle hypothesis of neurotransmitter release. For example, biochemical studies have shown that neurotransmitter is concentrated in vesicles, and fusion of vesicles to the plasma membrane and their depletion in the terminal cytoplasm after action potentials have been shown with electron microscopic techniques. 3.6 mV 47 msec A 1 mV 20 msec B •Fig. 6.5 A, SpontaneousmEPPsrecordedataneuromuscularjunctioninafiberoffrogextensordigitorumlongus.B, EPPsevokedbynervestimulationunderlow-[Ca++]conditions,whichreducetheprobabilityoftransmitterrelease.Thesmall-amplitudeEPPsevokedundertheseconditionsvaryinamplitudeinastep-likemanner,wherethesizeofthestepisequaltothesmallestEPP,whichinturnequalsthesizeofthemEPPs.(Notethatintheseconditionsthestimulusoftenfailstoevokeanyresponse,asindicatedbyaflatresponse.)(A, DatafromFattP,KatzB.Nature 1950;166:597;B, datafromFattP,KatzB.J Physiol 1952;117:109.)


Physiology_Levy

Physiology_Levy. The small vesicles that contain nonpeptide neurotransmitters can fuse with the presynaptic membrane only at specific sites called active zones. To become competent to fuse with the presynaptic membrane at an active zone, a small vesicle must first dock at the active zone and then undergo a priming process. Once primed the vesicle can fuse and release its transmitter into the synaptic cleft in response to an increase in local cytoplasmic [Ca++]. On the order of 25 proteins may play roles in docking, priming, and fusion. Some of these proteins are cytosolic, whereas others are proteins associated with the vesicle membrane or the presynaptic plasma membrane. The functions of most of these proteins are incompletely understood; however, knowledge of the molecular details of transmitter release has increased dramatically in recent years.


Physiology_Levy

Physiology_Levy. As with other exocytotic processes, neurotransmitter release involves SM (sec1/Munc18-like) and SNARE (soluble N-ethyl maleimide-sensitive factor attachment protein receptor) proteins: v-SNARES in the vesicle membrane and t-SNARES in the (target) presynaptic plasma membrane. Zipper-like interactions between synaptobrevin (a v-SNARE) and syntaxin and SNAP-25 (both are t-SNARES) with the assistance of SM proteins bring the vesicle membrane and the presynaptic plasma membrane close together before fusion. The SNARE proteins are targets for various botulinum toxins, which disrupt synaptic transmission, thus demonstrating their critical role in this process. Nevertheless, they do not bind Ca++ , so another protein must be the Ca++ sensor that triggers the actual fusion event. Evidence indicates that a synaptotagmin protein is almost certainly the Ca++ sensor and, even more specifically, that the second of its two cytoplasmic domains contains the Ca++ binding site. Interestingly,


Physiology_Levy

Physiology_Levy. indicates that a synaptotagmin protein is almost certainly the Ca++ sensor and, even more specifically, that the second of its two cytoplasmic domains contains the Ca++ binding site. Interestingly, synaptotagmins differ in their kinetics, and brain regions vary as to which synaptotagmin family member acts as the Ca++ sensor for vesicular fusion. Thus, differential expression of synaptotagmin genes in neurons may be a mechanism to adapt the kinetics of vesicle release and thereby tailor the specific characteristics of synaptic transmission to the functional needs of each CNS region.


Physiology_Levy

Physiology_Levy. Calcium channels are located in the active zone membrane at sites adjacent to the docked vesicles. When they open, a small area of high [Ca++], a microdomain is created at the active zone. This local high concentration (which lasts for less than a millisecond), allows the rapid binding of Ca++ to synaptotagmin, triggering the fusion of a docked vesicle and allowing release of its neurotransmitter. Despite the multiple steps involved, the process of vesicular release at a synapse is extremely rapid because of the close proximity of the molecular apparatuses involved to each other. Indeed, the time from Ca++ influx to vesicle fusion is about 0.2 msec.


Physiology_Levy

Physiology_Levy. “Reserve” pool Competence maturation Fusion and collapse Coated-vesicle retrieval “Recycling” pool “Docked” “Primed” (?) (2) (2') (3') ? ? (1) (3) (4) (5) “Cocked” (?) Armed Fire! ? ? “Readily releasable” pool (RRP) Kiss... Run! Kiss-and-run fusion Phosphorylations, Ca++ fusion machine assembly ? ?? Ca++ •Fig. 6.6 Vesiclerecyclingpathways.Synapticvesicleshavebeenthoughttofusewiththemembranewhileemptyingtheircontentsandthenberecycledbyformingclathrin-coatedpitsthatareendocytosedtoformcoatedvesicles(1→ [2or2′]→ 3′→ 1).Analternativepathwaythatmayallowmorerapidrecyclingofvesicleshasbeenproposed.Thispathway,called“kissandrun,”involvesonlytransientfusionofthevesicletothepresynapticmembranetoformaporethroughwhichthevesiclecontentsmaybeemptied,followedbydetachmentofthevesiclefromthemembrane(1→ 2→ 3→ 4→ 5→ 1).(RedrawnfromValtortaF,MeldolesiJ,FesceR.Trends Cell Biol 2001;11:324.)


Physiology_Levy

Physiology_Levy. During synaptic transmission, vesicles must fuse with the plasma membrane to release their contents into the synaptic cleft. However, there must be a reverse process; otherwise, not only would it be hard to sustain the vesicle population, but the presynaptic membrane’s surface area would also grow with each bout of synaptic transmission, and its molecular content and functionality would likewise change (because, as just discussed, the protein content of the vesicle membrane is distinct from that of the terminal membrane).


Physiology_Levy

Physiology_Levy. There appear to be two distinct mechanisms by which vesicles are retrieved after release of their neurotransmitter content (Fig. 6.6 ). One mechanism is the endocytotic pathway commonly found in most cell types. Coated pits are formed in the plasma membrane, which then pinch off to form coated vesicles within the cytoplasm of the presynaptic terminal. These vesicles then lose their coat and undergo further transformations (i.e., acquire the correct complement of membrane proteins and be refilled with neurotransmitter) to become once again synaptic vesicles ready for release. Evidence for a second, more rapid recycling mechanism has been obtained (see


Physiology_Levy

Physiology_Levy. Evidence for a second, more rapid recycling mechanism has been obtained (see Fig. 6.6 ). It involves transient fusion of the vesicle to the synaptic membrane and has been called “kiss and run.” In this case, fusion of the vesicle with the synaptic membrane leads to the formation of a pore through which the transmitter is expelled, but there is no wholesale collapse of the vesicle into the membrane. Instead, the duration of the fusion is very brief, after which the vesicle detaches from the plasma membrane and reseals itself. Thus, the vesicle membrane retains its molecular identity. Its contents can then simply be replenished, thereby making the vesicle ready for use again.


Physiology_Levy

Physiology_Levy. The relative importance of these two mechanisms is still being debated. However, at central synapses, which tend to be small and contain relatively few vesicles in comparison to the neuromuscular junction, the rapid time course of the kiss-and-run mechanism may help avoid the problem of vesicle depletion and the consequent failure of synaptic transmission during periods of high activity (many neurons in the CNS can show firing rates of several hundred hertz, and a few types of neuron can fire at rates of ≈ 1000 Hz).


Physiology_Levy

Physiology_Levy. Following vesicle fusion the neurotransmitter molecules are released and diffuse across the synaptic cleft (a very rapid process) and bind to receptors on the postsynaptic membrane. This binding leads to the opening (or less often the closing) of ion channels. These channels are termed ligand-gated because their opening and closing are primarily controlled by the binding of neurotransmitter. This mechanism can be contrasted with that of the voltage-gated channels underlying the action potential, whose opening and closing are determined by the membrane potential. However, there are some channels, most notably the NMDA (N-methyl-Daspartate) channel, that are both ligand and voltage gated.


Physiology_Levy

Physiology_Levy. It is also worth noting here that what follows in this section refers to what happens when neurotransmitter binds to receptors in which the ion channel is part of the receptor itself. These receptors are referred to as ionotropic receptors and underlie what is now called “fast” synaptic transmission. There is also “slow” synaptic transmission, mediated by what are called metabotropic receptors, in which the receptor and ion channel are not part of the same molecule, and binding of neurotransmitter to the receptor initiates biochemical cascades that lead to postsynaptic potentials with slow onsets (see the section Receptors for details). Despite the differing time courses, many of the same basic principles apply to both types of postsynaptic potential.


Physiology_Levy

Physiology_Levy. EPSPs. As stated earlier, the binding of neurotransmitter generally changes the membrane potential of the postsynaptic cell, and these changes are referred to as EPSPs when they increase the excitability of the neuron and IPSPs when they inhibit the neuron from firing action potentials. EPSPs are always depolarizing potentials, and IPSPs are usually hyperpolarizing.


Physiology_Levy

Physiology_Levy. Once a ligand-gated channel is open, the direction of current flow through it is determined by the electrochemical driving force for the permeant ion(s). It turns out that the pores of most channels that underlie EPSPs are relatively large and therefore allow passage of most cations with similar ease. As an example, consider the acetylcholinegated channel that is opened at the neuromuscular junction. Na+ and K+ are the major cations present (Na+ extracellularly and K+ intracellularly); therefore, the net current through the channel is approximately the sum of the Na+ and K+ currents (Inet = INa + IK). Recall that the current through a channel from a particular ion is dependent on two factors: the conductance of the channel to the ion and the driving force on the ion. This relationship is expressed by the equation


Physiology_Levy

Physiology_Levy. Equation 6.1 where gx is the conductance of the channel to ion x, Vm is the membrane potential, and Ex is the Nernst equilibrium potential for ion x. In this case gx is similar for Na+ and K+ , so the main determinant of net current is the relative driving forces (Vm − Ex). If the membrane is at its resting potential (typically around −70 mV), there is a strong driving force (Vm − ENa) for Na+ to enter the cell because this potential is far from the Na+ Nernst potential (about +55 mV), whereas there is only a small driving force for K+ to leave the cell because Vm is close to the K+ Nernst potential (about −90 mV). Thus, if acetylcholine-gated channels open when the membrane is at its resting potential, a large inward Na+ current and a small outward K+ current will flow through the acetylcholine channel, thereby resulting in a net inward current, which acts to depolarize the membrane.


Physiology_Levy

Physiology_Levy. The net inward current that results from opening such channels is called the excitatory postsynaptic current (EPSC).


Physiology_Levy

Physiology_Levy. Fig. 6.7A contrasts the time course of the EPSC and the resulting EPSP for fast synaptic transmission. The EPSC is much shorter (≈1 to 2 msec in duration) and corresponds to the time the channels are actually open. The short duration of the EPSC is due to the fact that the released neurotransmitter remains in the synaptic cleft for only a short while before being either enzymatically degraded or taken up by either glia or neurons. Binding and unbinding of a neurotransmitter to its receptor take place rapidly, so once its concentration falls in the cleft, the postsynaptic receptor channels rapidly close as well and terminate the EPSC. Note how the end of the EPSC corresponds to the peak of the EPSP, which is followed by a long tail. The duration of the tail and the rate of the decay in EPSP amplitude reflect the passive membrane properties of the cell (i.e., its RC properties) (see ). In slow synaptic transmission, the duration of the EPSP reflects the activation and deactivation of


Physiology_Levy

Physiology_Levy. amplitude reflect the passive membrane properties of the cell (i.e., its RC properties) (see ). In slow synaptic transmission, the duration of the EPSP reflects the activation and deactivation of biochemical processes more than the membrane properties. The long duration of even fast EPSPs (relative to EPSCs and action potentials) is functionally important because it allows EPSPs to overlap and thereby summate. Such summation is central to the integrative properties of neurons (see the next section,


Physiology_Levy

Physiology_Levy. Normally an EPSP depolarizes the membrane, and if this depolarization reaches threshold, an action potential is generated. However, consider what happens if the channels underlying the action potential are blocked and the membrane of the postsynaptic cell is experimentally depolarized by injecting current through an intracellular electrode. Because the membrane potential is now more positive, the driving force for Na+ is decreased and that for K+ increased. If the synapse is activated at this point, the net current through the receptor channel (the EPSC) will be smaller because of changes in the relative driving force. This implies that if the membrane potential is depolarized enough, there will be a point at which the Na+ and K+ currents through the channel are equal and opposite, and thus there is no net current and no EPSP. If the membrane is depolarized beyond this point, there is a net outward current through the receptor channels and the membrane will hyperpolarize (i.e., the


Physiology_Levy

Physiology_Levy. thus there is no net current and no EPSP. If the membrane is depolarized beyond this point, there is a net outward current through the receptor channels and the membrane will hyperpolarize (i.e., the EPSP will be negative). Thus, the potential at which there is no EPSP (or EPSC) is known as the reversal potential. For excitatory synapses, the reversal potential is usually around 0 mV (±10 mV), depending on the synapse (see


Physiology_Levy

Physiology_Levy. Fig. 6.7B–C It is worth noting that a reversal potential is a key criterion for demonstrating the chemical-gated as opposed to the voltage-gated nature of a synaptic response because currents through voltage-gated channels do not reverse, except at the Nernst potential of the ion for which they are selective (and then only if the channel is open at that potential). Consequently, beyond a certain membrane potential, no current will flow through voltage-gated channels because they will be closed. In contrast, ligand-gated channels can be opened at any membrane potential and thus can always have a net current flow through them, except at one specific voltage, the reversal potential.


Physiology_Levy

Physiology_Levy. 0.1 msec/div Action potentials triggered by EPSP 5 mV ˜V •Fig. 6.7 PropertiesofEPSPs.A, TimecourseofafastEPSPcomparedwiththatoftheunderlyingEPSC.Inmanycases,suchasthisone,theEPSCismuchshorterthantheEPSP;however,sometimestheEPSCcanhaveafairlyextensivetail.B, IntracellularlyrecordedEPSPsatdifferentlevelsofdepolarization.EPSPswereevokedinmotorneuronsbystimulationofIaafferents.Thenumbertotheleftofeachtraceindicatesthemembranepotentialinducedbyinjectionofcurrentthroughtheelectrode.Atinitialmembranepotentialsof−42and−60mV,theEPSPtriggeredanactionpotential.Atmoredepolarizedlevels,Na+ channelsareinactivated,sonospikeoccurs.C, TodeterminetheEPSPreversalpotential,theinitialmembranepotentialisplottedagainstthesizeoftheEPSP(ΔV).ThisEPSPreversedat−7mV.(A, DatafromCurtisDR,EcclesJC.J Physiol 1959;145:529;B, datafromCoombsJSetal.J Physiol 1955;130:374.)


Physiology_Levy

Physiology_Levy. IPSPs. Like EPSPs, IPSPs are triggered by the binding an action potential (otherwise it would increase the prob-of neurotransmitter to receptors on the postsynaptic ability of the cell spiking and by definition be an EPSP). It membrane and typically involve an increase in membrane may seem counterintuitive that something that depolarizes permeability as a result of the opening of ligand-gated the membrane can still be considered inhibitory, but if channels. They differ in that IPSP channels are permeable it decreases the probability of spiking, then it is indeed to only a single ionic species, either Cl− or K+ . Thus, IPSPs inhibitory (a further explanation is given in the Synaptic will have a reversal potential equal to the Nernst potential Integration section). of the ion carrying the underlying current. Typically the In sum, starting from the resting membrane potential, Nernst potential for these ions is somewhat negative relative EPSPs are always depolarizing, IPSPs can be either


Physiology_Levy

Physiology_Levy. current. Typically the In sum, starting from the resting membrane potential, Nernst potential for these ions is somewhat negative relative EPSPs are always depolarizing, IPSPs can be either depolarto the resting potential, so when IPSP channels open, there izing or hyperpolarizing, and a hyperpolarizing potential is is an outward flow of current through them that results in always an IPSP. Thus, the key distinction between inhibitory hyperpolarization of the membrane (see


Physiology_Levy

Physiology_Levy. Fig. 6.3 ). and excitatory synapses (and IPSPs and EPSPs) is how they


Physiology_Levy

Physiology_Levy. However, in some cells, activation of an inhibitory affect the probability of the cell firing an action potential: synapse may produce no change in potential (if the mem-EPSPs increase the probability, whereas IPSPs decrease the brane potential equals the Nernst potential for Cl− or K+) or probability. may actually result in a small depolarization. Nevertheless, Safety factor. Synapses between cells vary in strength and in both these cases, the reversal potential for the IPSP thus in the size of the PSP generated in the postsynaptic cell. is still negative with regard to the threshold for eliciting Many factors determine synaptic strength, including the size and number of synaptic contacts between two cells, its activity level and past history, and the probability of vesicle fusion for the synapse. For excitatory synapses, the strength of the synapse may be quantified by what is known as its safety factor (the ratio of EPSP amplitude to the amplitude needed to reach the threshold to


Physiology_Levy

Physiology_Levy. synapse. For excitatory synapses, the strength of the synapse may be quantified by what is known as its safety factor (the ratio of EPSP amplitude to the amplitude needed to reach the threshold to trigger an action potential). Most synapses have low safety factors (<1), and thus it takes the summed EPSPs of multiple active synapses to trigger an action potential in the postsynaptic neuron. This summation process is at the core of synaptic integration, which is taken up in the next section. Synapses with high (>1) safety factors exist, however, and the neuromuscular junction is one prominent example. When a motor neuron action potential triggers release of neurotransmitter at the neuromuscular junction, an end plate potential (EPP; the equivalent of an EPSP in a neuron) is generated in the muscle fiber. The EPP is so large that under normal circumstances it depolarizes the sarcolemma well above the action potential threshold and thus always triggers a spike, leading to contraction of


Physiology_Levy

Physiology_Levy. muscle fiber. The EPP is so large that under normal circumstances it depolarizes the sarcolemma well above the action potential threshold and thus always triggers a spike, leading to contraction of the muscle cell. A high safety factor makes sense for the neuromuscular junction because each muscle cell is contacted by only a single motor neuron, and if that motor neuron is firing, the nervous system has basically made the decision to contract that muscle. In certain diseases of the neuromuscular junction, such as myasthenia gravis and Lambert-Eaton syndrome, the EPPs are reduced such that the safety factor can fall below 1, and thus the EPPs sometimes fail to trigger action potentials in the muscle fibers, leading to weakness.


Physiology_Levy

Physiology_Levy. The overall effect of a particular synapse is dependent on its location. To understand this concept fully, we must first recall that action potentials are typically generated at the initial segment of the cell because it has the highest density of voltage-gated Na+ channels and therefore the lowest threshold for initiation of a spike. Thus, it is the summed amplitudes of the synaptic potentials at this point, the initial segment, that is critical for the decision to spike. EPSPs generated by synapses close to the initial segment (i.e., synapses onto the soma or proximal dendrites) will result in a larger depolarization at the initial segment than will EPSPs generated by synapses on distal dendrites ( Fig.


Physiology_Levy

Physiology_Levy. 6.8A single action potential in axon 2 versus 1). This is because the cell membrane is leaky and synaptic currents are generated locally at the synapse, so even if two synapses generate a local EPSC of the same size, less of the initial current will arrive at the initial segment from the more distal synapse than from the more proximal one, thereby resulting in the generation of a smaller EPSP at the initial segment by the distal synapse (see discussion of length constant in ). Thus, the synapse’s spatial location in the dendritic tree is an important determinant of its efficacy. However, as already mentioned, EPSPs generated by most CNS synapses, even those in favorable positions (i.e., close to the initial segment), are too small by themselves to reach •Fig. 6.8 SynapticintegrationofEPSPsrecordedattheaxonhillockadjacenttotheinitialsegment.A, ComparisonofEPSPsevokedbyproximalversusdistalsynapses(2versus1).B,


Physiology_Levy

Physiology_Levy. are too small by themselves to reach •Fig. 6.8 SynapticintegrationofEPSPsrecordedattheaxonhillockadjacenttotheinitialsegment.A, ComparisonofEPSPsevokedbyproximalversusdistalsynapses(2versus1).B, Temporalsummation.EPSPsinresponsetotwospikesinthesameaxonoccurringinrapidsuccession(axon2).C, Spatialsummation.Responsesevokedbysynapsesthatareelectricallydistantfromeachother(1and3).D, Sublinearsummationoftwosynapseslocatedneareachotherbecauseofshunting(2and4).


Physiology_Levy

Physiology_Levy. the spiking threshold in the postsynaptic cell, as illustrated in Fig. 6.8A , where an action potential in either axon 1 (distal) or 2 (proximal) both produce EPSPs that are too small to trigger a spike. Thus, generally the summed EPSPs from multiple synapses are required to reach threshold and trigger a spike. The requirement for multiple EPSPs to summate in order to trigger a spike is what makes the relatively long duration of EPSPs so important. Temporal summation refers to the fact that EPSPs that are separated by a latency less than their duration can sum. This is illustrated in Fig. 6.8B , where the same synapse is activated multiple times in rapid succession (axons can fire action potentials at rates well over 100 Hz); in this situation, successive EPSPs will be less than 10 msec apart and therefore overlap and sum. Note the higher amplitude of the second peak.


Physiology_Levy

Physiology_Levy. Spatial summation refers to the fact that synaptic potentials generated by different synapses can interact. For example, in Fig. 6.8 , suppose axon 1 and 3 each fire an action potential but at widely separated times. Each produces an EPSP that depolarizes the cell but is too small to reach threshold (see Fig. 6.8C , EPSP1, EPSP3). Instead, if both axons fire within a short enough time of each other, their effect can be additive, as shown in Fig. 6.8C (EPSP 1+3). The combined EPSP amplitude may then reach threshold and lead to spiking of the cell. If the EPSPs generated by axons 1 and 3 were simultaneous, then we would have an example of pure spatial summation. In the example shown, however, the times of the two EPSPs were slightly separated, thus we have both spatial and temporal summation present. The fact that EPSPs have a long time course (when compared with action potentials or the underlying EPSCs) facilitates both types of synaptic integration.


Physiology_Levy

Physiology_Levy. In the foregoing example, the combined EPSP was approximately the linear summation of the two individual EPSPs evoked by action potentials in axons 1 and 3. This is the case when two synapses are far apart. If the two synapses are close together, such as for axons 2 and 4 (see Fig. 6.8D ), the summation becomes less than linear because of what is known as a shunting effect. That is, when synapse 2 is active, channels are opened in the cell membrane, which means that it is more leaky. Therefore, when synapse 4 is also active, more of its EPSC will be lost (shunted) through the dendritic membrane, and less current will be left to travel down the dendrite to the initial segment. The result is that synapse 4 causes a smaller EPSP at the initial segment than it would have generated in isolation. Nevertheless, the combined EPSP is still larger than an EPSP caused by either synapse 2 or 4 alone.


Physiology_Levy

Physiology_Levy. Where do IPSPs fit into synaptic integration? In many cases one can think of them as negative EPSPs. Thus, whereas EPSPs add together to help bring the membrane potential up to and beyond the spiking threshold, IPSPs subtract from the membrane potential to make it more negative and therefore further from threshold. In deciding whether to spike, a cell adds up the ongoing EPSPs and subtracts the IPSPS to determine whether the sum reaches threshold. As with an EPSP, the efficacy of an IPSP varies with its location.


Physiology_Levy

Physiology_Levy. In addition to subtracting algebraically from the membrane potential, IPSPs exert an inhibitory action via the shunting mechanism, just as was described earlier for EPSPs. That is, while the IPSP channels are open, they make the membrane more leaky (i.e., lower its resistance) and thereby reduce the size of EPSPs, thus making them less effective. This shunting mechanism explains how IPSPs that do not change the membrane potential—or even those that slightly depolarize it—can still decrease the excitability of the cell. An alternative way to look at this effect is to view each synapse as a device that tries to bring the membrane potential to its own equilibrium potential. Because this potential is below the action potential threshold in the case of IPSPs, IPSPs make it harder for the cell to spike.


Physiology_Levy

Physiology_Levy. Thus far the interaction of synaptic potentials has been presented under the assumption that the postsynaptic cell membrane is passive (i.e., it acts as though it were simply resistors and capacitors in parallel with each other). However, it is clear that the dendrites and somas of most, if not all, neurons contain active elements (i.e., gated channels) that can amplify and alter EPSPs and IPSPs. For example, a distal EPSP can have a larger-than-expected effect if the EPSP activates dendritically-located voltage-gated Na+ or Ca++ channels that boost its amplitude or even generate propagated dendritic action potentials. Another example is Ca++-activated K+ channels that are present in the dendrites of some neurons. These channels are activated by the influx of Ca++ either through synaptic channels or via dendritic voltage-gated Ca++ channels opened by EPSPs and can cause long-lasting hyperpolarizations that effectively make the cell inexcitable for tens to hundreds of milliseconds. As


Physiology_Levy

Physiology_Levy. channels or via dendritic voltage-gated Ca++ channels opened by EPSPs and can cause long-lasting hyperpolarizations that effectively make the cell inexcitable for tens to hundreds of milliseconds. As a final example, there are some Ca++ channels that underlie a low-threshold Ca++ spike. These channels are normally inactive at resting membrane potentials, but the hyperpolarization that results from a large IPSP can de-inactivate them and allow them to open (and produce a spike) after termination of the IPSP. In this case “inhibition” actually increases the cell’s excitability. In sum, synaptic integration is a highly complex, nonlinear process. Nevertheless, the basic principles just described remain at its core.


Physiology_Levy

Physiology_Levy. Modulation of Synaptic Activity Integration of synaptic input by a postsynaptic neuron, as described in the previous section, represents one aspect of the dynamic nature of synaptic transmission. A second aspect is that the strength of individual synapses can vary as a function of their use or activity. That is, a synapse’s current functional state reflects, to some extent, its history.


Physiology_Levy

Physiology_Levy. Activation of a synapse typically produces a response in the postsynaptic cell (i.e., a postsynaptic potential) that will be roughly the same each time, assuming the postsynaptic cell is in a similar state. Certain patterns of synaptic activation, however, result in changes in the response to subsequent activation of the synapse. Such use-related changes may remain for short (milliseconds) or long (minutes to days) durations and may be either a potentiation or suppression of the synapse’s strength. These changes probably underlie cognitive abilities such as learning and memory. Thus, the processes by which activity results in changes in a synapse’s efficacy are a critical feature of synaptic transmission. When a presynaptic axon is stimulated twice in rapid succession, it is often found that the postsynaptic potential evoked by the second stimulus are larger in amplitude than the one evoked by the first (Fig. 6.9 ). This increase


Physiology_Levy

Physiology_Levy. A Facilitation B Facilitation C Posttetanic potentiation 3 msec 10 msec 1/sec 5/sec 10/sec 12.5/sec 31.2/sec 25/sec 1 mV 4 sec tetanic stimulation 8 sec 14 sec 27 sec Time after tetanic stimulation •Fig. 6.9 A, Facilitationataneuromuscularjunction.EPPsataneuromuscularjunctionintoadsartoriusmusclewereelicitedbysuccessiveactionpotentialsinthemotoraxon.Neuromusculartransmissionwasdepressedby5mMMg++ and2.1mMcuraresothatactionpotentialsdidnotoccur.B, EPPsatafrogneuromuscularjunctionelicitedbyrepetitivelystimulatingthemotoraxonatdifferentfrequencies.Notethatfacilitationfailedtooccuratthelowestfrequencyofstimulation(1/sec)andthatthedegreeoffacilitationincreasedwithincreasingfrequencyofstimulationintherangeoffrequencyused.Neuromusculartransmissionwasinhibitedbybathingthepreparationin12to20mMMg++ .C,


Physiology_Levy

Physiology_Levy. .C, Posttetanicpotentiationatafrogneuromuscularjunction.ThetoptwotracesindicatecontrolEPPsinresponsetosingleactionpotentialsinthemotoraxon.SubsequenttracesindicateEPPsinresponsetosingleactionpotentialsaftertetanicstimulation(50impulses/secfor20seconds)ofthemotorneuron.Thetimeintervalbetweentheendoftetanicstimulationandthesingleactionpotentialisshownoneachtrace.Themusclewastreatedwithtetrodotoxintopreventgenerationofactionpotentials.(A, RedrawnfromBelnaveRJ,GagePW.J Physiol 1977;266:435;B, redrawnfromMagelbyKL.J Physiol 1973;234:327;C, redrawnfromWeinrichD.J Physiol 1971;212:431.) is known as paired-pulse facilitation (PPF). Note PPF is distinct from temporal summation, in which two EPSPs overlap and sum to a larger response; with PPF the second EPSP itself is greater in size. If one plots the relative size of the two postsynaptic potentials (PSPs) as a function of the time between two stimuli, the amount of increase in the second PSP will be seen to depend on the time interval.


Physiology_Levy

Physiology_Levy. plots the relative size of the two postsynaptic potentials (PSPs) as a function of the time between two stimuli, the amount of increase in the second PSP will be seen to depend on the time interval. Maximal facilitation occurs at around 20 msec, followed by a gradual reduction in facilitation as the interstimulus interval continues to increase; with intervals of several hundred milliseconds, the two PSPs are equal in amplitude and no facilitation is observed. Thus, PPF is a relatively rapid and short-lasting change in synaptic efficacy.


Physiology_Levy

Physiology_Levy. Posttetanic potentiation (PTP) is similar to PPF; however, in this case the responses are compared before and after stimulation of the presynaptic neuron tetanically (tens to hundreds of stimuli at a high frequency). Such a tetanic stimulus train causes an increase in synaptic efficacy (see Fig. 6.9C ). PTP, like PPF, is an enhancement of the postsynaptic response, but it lasts longer: tens of seconds to several minutes after the cessation of tetanic stimulation.


Physiology_Levy

Physiology_Levy. Fig. 6.9C ). PTP, like PPF, is an enhancement of the postsynaptic response, but it lasts longer: tens of seconds to several minutes after the cessation of tetanic stimulation. Numerous experiments have shown that PPF and PTP are the result of changes in the presynaptic terminal and do not generally involve a change in the sensitivity of the postsynaptic cell to transmitter. Rather, the repeated stimulation leads to an increased number of quanta of transmitter being released. This increase is thought to be due to residual amounts of Ca++ that remain in the presynaptic terminal after each stimulus and help potentiate subsequent release of transmitter. However, the exact mechanism or mechanisms by which this residual Ca++ enhances release is not yet clear. The residual Ca++ does not, however, appear to act simply by binding to the same sites as the Ca++ that enters at the active zone and directly triggers vesicle fusion in response to the action potential.


Physiology_Levy

Physiology_Levy. Use of a synapse can also lead to a short-term depression in its efficacy. Most commonly, the postsynaptic cell at such a fatigued or depressed synapse responds normally to transmitter applied from a micropipette; hence, as was the case for PPF and PTP, the change is presynaptic. In general, the depression is thought to reflect depletion of the number of releasable presynaptic vesicles. Thus, short-term depression of synaptic transmission is most often and most easily seen at synapses in which the probability of release after a single stimulus is high and under conditions that favor release (i.e., high [Ca++]). A postsynaptically related cause of synaptic depression can be desensitization of the receptors in the postsynaptic membrane.


Physiology_Levy

Physiology_Levy. Both potentiation and depressive processes can occur at the same synapse. So in general, the type of modulation observed will depend on which process dominates. This in turn can reflect stimulus parameters, local ionic conditions, and the properties of the synapse. In particular, synapses have different baseline probabilities for releasing vesicles. Synapses with a high release probability will be more likely to show poststimulus depression, whereas those with low release probability are less likely to deplete their vesicle store and thus can be facilitated more easily. Sometimes mixed responses can occur. For example, during a tetanic stimulus train a synapse may show a depressed response, but after the train the synapse can show posttetanic facilitation once the vesicles are recycled.


Physiology_Levy

Physiology_Levy. Just as the postsynaptic membrane contains receptors for neurotransmitters, so does the presynaptic membrane. When these presynaptic receptors bind neurotransmitter, they cause events that can modulate subsequent release of transmitter by the terminal. There are several sources of transmitter that bind to presynaptic receptors: it can be the transmitter released by the terminal itself (i.e., self-modulation, in which case the receptors are referred to as autoreceptors), it can be released by another presynaptic terminal that synapses onto the terminal (a serial synapse), or it can be a nonsynaptically acting neurotransmitter (see the section


Physiology_Levy

Physiology_Levy. Presynaptic receptors can be either ionotropic or metabotropic. In the latter case, recall that their action will be relatively slow in onset and long in duration and the effect will depend on the specific second messenger cascades that are activated. Such cascades can ultimately regulate presynaptic voltage-gated Ca++ and K+ channels and other presynaptic proteins and thereby alter the probability of vesicle release. In contrast, activation of presynaptic ionotropic receptors will directly alter the electrical properties of the presynaptic terminal and cause rapid transient (millisecond time scale) changes in the probability of vesicle release (although they too can have much longer lasting effects). Binding of an ionotropic receptor will open channels in the presynaptic terminal and thereby alter the amount of transmitter released by an action potential.


Physiology_Levy

Physiology_Levy. Presynaptic inhibition refers to occasions when binding of presynaptic receptors leads to a decrease in release of transmitter, and it can be the result of one or more mechanisms (Fig. 6.10 ). First, opening of channels decreases membrane resistance and creates a current shunt. The shunt acts to divert the current associated with the action potential from the active zone membrane and thereby lessens the depolarization of the active zone, which results in less activation of Ca++ channels, less Ca++ entry, and less release of transmitter. A second mechanism is the change in membrane potential caused by the opening of presynaptic •Fig. 6.10 Presynapticinhibition.Activeregenerationofactionpotentialsinaxon2endsatthelastnode.Theactionpotentialisthenpassivelyconductedintotheterminal.Axon1makesanaxoaxonicsynapsewithaxon2.Activationofthissynapsereducesconductionoftheactionpotentialinaxon2totheactivezoneofitssynapticterminalbymechanismsdescribedinthetext.Thisreducestheopeningofvoltage-gatedCa++


Physiology_Levy

Physiology_Levy. channelsandthereforereleaseofneurotransmitter.


Physiology_Levy

Physiology_Levy. ionotropic channels. If a small depolarization is the result, there will be inactivation of voltage-gated Na+ channels and thereby lessening of the action potential–associated current and transmitter release. Presynaptic γ-aminobutyric acid A receptors (GABAA) occur in the spinal cord and mediate presynaptic inhibition by these mechanisms. They control Cl− channels. Generally, opening of Cl− channels generates a hyperpolarization. However, in the presynaptic terminal, the [Cl−] gradient is such that Cl− flows out of the cell and generates a small depolarization. This depolarization is small enough that it does not cause significant opening of voltage-gated Ca++ channels; otherwise, it would increase release of transmitter (presynaptic facilitation). In fact, there are other receptors that control cation channels and create large depolarizations, thereby increasing the release of transmitter. In addition, presynaptic nicotinic acetylcholine receptors control a cation channel that is


Physiology_Levy

Physiology_Levy. control cation channels and create large depolarizations, thereby increasing the release of transmitter. In addition, presynaptic nicotinic acetylcholine receptors control a cation channel that is permeable to Ca++ . By allowing additional entry of Ca++ , these receptors increase the release of transmitter from the terminal.


Physiology_Levy

Physiology_Levy. Repetitive stimulation of certain synapses in the brain can also produce more persistent changes in the efficacy of transmission at these synapses, a process called long-term potentiation or long-term depression. Such changes can persist for days to weeks and are believed to be involved in the storage of memories.


Physiology_Levy

Physiology_Levy. The increased synaptic efficacy that occurs in long-term potentiation probably involves both presynaptic (greater transmitter release) and postsynaptic (greater sensitivity to transmitter) changes, in contrast to the short-term changes that involve changes only in presynaptic function. Entry of calcium into the postsynaptic region is an early step required for initiating the changes that result in long-term enhancement of the response of the postsynaptic cell to neurotransmitter. Entry of calcium occurs through NMDA and some AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (classes of glutamate receptors; see the section Receptors). Entry of Ca++ is believed to activate Ca++-calmodulin kinase II, a multifunctional protein kinase that is present in very high concentrations in postsynaptic densities. In the presence of high [Ca++], this kinase can phosphorylate itself and thereby become active. Calciumcalmodulin kinase II is believed to phosphorylate proteins that


Physiology_Levy

Physiology_Levy. in postsynaptic densities. In the presence of high [Ca++], this kinase can phosphorylate itself and thereby become active. Calciumcalmodulin kinase II is believed to phosphorylate proteins that are essential for the induction of long-term potentiation. Long-term potentiation may also have an anatomic component. After appropriate stimulation of a presynaptic pathway, the number of dendritic spines and the number of synapses on the dendrites of postsynaptic neurons may increase rapidly. Changes in the presynaptic nerve terminal may also contribute to long-term potentiation. The postsynaptic neuron may release a signal (nitric oxide has been suggested) that enhances release of transmitter by the presynaptic nerve terminal.


Physiology_Levy

Physiology_Levy. Neurotransmitters are the substances that mediate chemical signaling between neurons. For a substance to be considered a neurotransmitter, it must meet several generally recognized criteria. First, the substance must be demonstrated to be present in the presynaptic terminal, and the cell must be able to synthesize the substance. It should be released on depolarization of the terminal. Finally, there should be specific receptors for it on the postsynaptic membrane. This last criterion is certainly true for substances that act as synaptic transmitters, but if we want to be inclusive and include substances that act over widespread territories rather than just at a single synapse, the last criterion needs to be relaxed to include situations in which receptors are located at sites outside the synapse. Neurotransmission has been suggested as a general term to describe both synaptic and nonsynaptic signaling between cells.


Physiology_Levy

Physiology_Levy. More than 100 substances have been identified as potential neurotransmitters because they have met some (hence the “potential” qualifier) or all of these criteria. These substances can be subdivided into three major categories: small-molecule transmitters, peptides, and gaseous transmitters. The small-molecule neurotransmitters may be further subdivided into acetylcholine, amino acids, biogenic amines, and purines. The first three groups of small-molecule transmitters contain what are considered the classic neurotransmitters. Remaining transmitters are substances that are more recent additions to the list of neurotransmitters, although many of them have been known as biologically important molecules in other contexts for a long time.


Physiology_Levy

Physiology_Levy. In the peripheral nervous system, acetylcholine is the transmitter at neuromuscular junctions, at sympathetic and parasympathetic ganglia, and of the postganglionic fibers from all parasympathetic ganglia and a few sympathetic ganglia. It is also a transmitter within the CNS, most prominently of neurons in some brainstem nuclei, in several parts of the basal forebrain (septal nuclei and nucleus basalis) and basal ganglia, and in the spinal cord (e.g., motor neuron axon collaterals). Cholinergic neurons from the basal forebrain areas project diffusely throughout the neocortex and to the hippocampus and amygdala, and they have been implicated in memory functions. Indeed, degeneration of these cells occurs in Alzheimer’s disease, a form of dementia in which memory function is gradually and progressively lost.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Acetylcholine is synthesized from acetyl coenzyme A and choline by the enzyme choline acetyltransferase, which is located in the cytoplasm of cholinergic presynaptic terminals. After synthesis, acetylcholine is concentrated in vesicles. After release, the action of acetylcholine is terminated by the enzyme acetylcholinesterase, which is highly concentrated in the synaptic cleft. Acetylcholinesterase hydrolyzes acetylcholine into acetate and choline. The choline is then taken up by an Na+ symporter in the presynaptic membrane for the resynthesis of acetylcholine. The extracellular enzymatic degradation of acetylcholine is unusual for a neurotransmitter inasmuch as the synaptic action of other classic neurotransmitters is terminated via reuptake by a series of specialized transporter proteins.


Physiology_Levy

Physiology_Levy. •Fig. 6.11 Glutamatetransportcycle.A, Schematicshowsthefateofglutamatereleasedfromapresynapticterminal.Distinctglutamatetransportersexistonthepresynapticandpostsynapticcellmembranesforreuptake.Inaddition,glialcellstakeupglutamateandconvertittoglutamine.Theglutamineisthenreleasedandtakenintothepresynapticterminal,whereitisconvertedbacktoglutamatebeforebeingrepackagedintosynapticvesicles.B, Schematicoftransportershowingdirectionofionflowassociatedwiththemovementofglutamateacrossthemembrane. A variety of amino acids function as neurotransmitters. The three most important are glutamate, glycine, and GABA.


Physiology_Levy

Physiology_Levy. A variety of amino acids function as neurotransmitters. The three most important are glutamate, glycine, and GABA. Glutamate is the neurotransmitter at the overwhelming majority of excitatory synapses throughout the CNS. Despite its ubiquity, it was initially difficult to identify specific neurons as glutamatergic because glutamate is present in all cells; it has a key role in multiple metabolic pathways, and it is a precursor to GABA, the major inhibitory neurotransmitter. Nevertheless, experimental results have now clearly established glutamate as the major excitatory CNS neurotransmitter. When applied to cells, it causes depolarization and is released from neurons, and specific receptors and transporters for it have been identified.


Physiology_Levy

Physiology_Levy. In addition to being the main excitatory neurotransmitter, glutamate is a potent neurotoxin at high concentrations. Thus, strict limitation of glutamate’s activity after its release from the presynaptic terminal is necessary, not only to allow normal synaptic transmission but also to prevent cell death. This task is accomplished by specialized membrane transporter proteins ( Fig. 6.11 At the Cellular Level box). GABA and glycine act as inhibitory neurotransmitters. GABA is the major inhibitory transmitter throughout the nervous system. GABA is produced from glutamate by a specific enzyme (glutamic acid decarboxylase) that is present only in neurons that use GABA as a transmitter. Thus, experimentally, it is possible to identify cells as inhibitory GABAergic neurons by using antibodies to this enzyme to mark them (immunolabeling, see


Physiology_Levy

Physiology_Levy. Fig. 6.1B ). Many local interneurons are GABAergic. In addition, several brain regions contain large numbers of GABAergic projection neurons. The most notable are the spiny neurons of the striatum and the Purkinje cells of the cerebellar cortex. The inhibitory nature of Purkinje cells was especially surprising because they represent the entire output of the cerebellar cortex, and thus cerebellar cortical activity basically functions to suppress the activity of its downstream targets (cerebellar and vestibular nuclei).


Physiology_Levy

Physiology_Levy. Glycine functions as an inhibitory neurotransmitter in a much more restricted territory. Glycinergic synapses are predominantly found in the spinal cord, where they represent approximately half of the inhibitory synapses. They are likewise present in the lower brainstem, cerebellum, and retina in significant numbers. Interestingly, glycine also has another synaptic function. At excitatory NMDA-type glutamate receptors, glycine must also be bound for the ion channel to open. Thus, it acts as a cotransmitter at these synapses. It was generally thought that under physiological conditions the extracellular glycine concentration was high enough that the glycine binding sites of the NMDA channel were always saturated, but recent results suggest that this may not always be true, which implies that fluctuations in glycine levels may also be an important modulator of NMDA-mediated synaptic transmission.


Physiology_Levy

Physiology_Levy. After GABA and glycine are released from the presynaptic terminal, they are taken back up into the nerve terminal and neighboring glia by high-affinity Na+-Cl−–coupled membrane transporters. These Na+-Cl− transporters are part of what is called the solute carrier 6 (SLC6) family of transporters that also includes those for the biogenic amine neurotransmitters, but it is distinct from those for glutamate. Transport of the neurotransmitter into the cell is accomplished by symport with two Na+ and one Cl− ion. Four GABA transporter (GAT1, GAT2, GAT3, and BGT1) genes have been identified; however, GAT1 and GAT3 are the ones that are highly expressed in the CNS. Depending on region and species, they may be expressed in neurons and/or in glia. There are two main glycine transporters, GlyT1 and GlyT2. GlyT1 is found predominantly on astrocytes and is present throughout the CNS. In contrast, GlyT2 is located on glycinergic nerve terminals and is largely restricted to the spinal cord,


Physiology_Levy

Physiology_Levy. and GlyT2. GlyT1 is found predominantly on astrocytes and is present throughout the CNS. In contrast, GlyT2 is located on glycinergic nerve terminals and is largely restricted to the spinal cord, brainstem, and cerebellum.


Physiology_Levy

Physiology_Levy. Many of the neurotransmitters in this category may be familiar because they have roles outside the nervous system, often as hormones. Among the amines known to act as neurotransmitters are dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), serotonin (5-hydroxytryptamine [5-HT]), and histamine. Dopamine, norepinephrine, and epinephrine are catecholamines, and they share a common biosynthetic pathway that starts with the amino acid tyrosine. Tyrosine is converted to L-dopa by the enzyme tyrosine hydroxylase. L-Dopa is then converted to dopamine by dopa-decarboxylase. In dopaminergic neurons, the pathway stops here. In noradrenergic neurons, another enzyme, dopamine β-hydroxylase, converts dopamine to norepinephrine. Epinephrine is obtained by adding a methyl group to norepinephrine via phenylethanolamineN-methyl transferase. In serotoninergic neurons, serotonin is synthesized from the essential amino acid tryptophan. Tryptophan is first converted to 5-hydroxytryptophan


Physiology_Levy

Physiology_Levy. via phenylethanolamineN-methyl transferase. In serotoninergic neurons, serotonin is synthesized from the essential amino acid tryptophan. Tryptophan is first converted to 5-hydroxytryptophan by tryptophan 5-hydroxylase, which is then converted to serotonin by aromatic L-amino acid decarboxylase. Finally, in histaminergic neurons the conversion of histidine to histamine is catalyzed by histidine decarboxylase.


Physiology_Levy

Physiology_Levy. Removal of synaptically released biogenic amines is generally accomplished by reuptake into glia and neurons via transporters belonging to the Na+-Cl−–dependent transporter family. The catecholamines are then degraded by two enzymes, monoamine oxidase and catechol Omethyltransferase. Atleastfivetransporters(EAAT1toEAAT5,inwhichEAAT standsforexcitatory amino acid transporter)thatcarryglutamateacrosstheplasmamembranehavebeenidentified.TheyareallpartoftheNa+-K+–dependentfamilyoftransporters.InwardmovementofeachglutamatemoleculeisdrivenbythecotransportofthreeNa+ ionsandoneH+ ionandthecountertransportofoneK+ ionoutofthecell(see


Physiology_Levy

Physiology_Levy. Within the CNS, nerve cells that use biogenic amines as neurotransmitters are primarily found within one of a few brainstem nuclei, most of which project rather diffusely throughout large areas of the brain. Noradrenergic neurons are primarily found in the locus coeruleus and nucleus subcoeruleus, which are located near each other in the dorsal part of the rostral pons. The neurons of the locus coeruleus project throughout the entire brain. Targets of the nucleus subcoeruleus are more limited but still widespread and include the pons, medulla, and spinal cord. (Norepinephrine is also important in the peripheral nervous system because it is used by postganglionic sympathetic cells.) Serotoninergic fibers arise from a series of nuclei located at the midline of the brainstem, known as the raphe nuclei. Similar to the noradrenergic fibers, serotoninergic fibers are distributed throughout most of the brain and spinal cord. Dopaminergic fibers arise from two main brainstem regions: the