November 18, 2009

Duke Researchers Find Explanation For Rapid Maturation Of Neurons At Birth


"Fetal neurons need hyperexcitability for proper development, because they are moving to the right places (in the brain) and forming the right connections," said Wolfgang Liedtke, M.D., Ph.D., assistant professor at the Duke Center for Translational Neuroscience and Klingenstein Fellow in Neuroscience. "But at birth, the brain has to undergo a developmental shift."

It does this by controlling a "pump" that drains chloride out of newborn neurons, making these highly chaotic, developing cells quiet down. Researchers at Duke University Medical Center have figured out the genetic control of the pump in rodents.


"The "chloride shift" is a process that changes newborn neurons and sets the stage for cognition," said Liedtke, who is also an attending physician at Duke Pain Clinics. "It is a fundamental mechanism for brain function."

The findings were published online in the Journal of Neuroscience on Nov. 19.

The researchers discovered why the pump is almost absent in the developing brain and then goes into high gear after birth: there's a dual-brake mechanism that keeps the chloride-transporter (pump) molecules in check during pregnancy.

Liedtke, lead author Michelle Yeo, Ph.D., and the rest of the team identified a set of DNA repressor elements that act as a pair of brakes. Together the two suppress the gene Kcc2, which is responsible for producing proteins for the transporter molecules that "pump" out the chloride.






Liedtke also noted that neuron maturation, in terms of the chloride shift, is faster in female rodents. "It's really true that girls mature faster than boys. In rodents, by the three-month mark after birth, there is no difference in chloride levels in neurons. The males catch up."


Image Caption: The figure shows a novel gene-regulatory mechanism of the neuronal chloride transporter, Kcc2, which is the only transporter that removes chloride molecules from cells. During mammalian development, chloride levels are high in neurons, but levels rapidly decrease around the time of birth when the Kcc2 transporter removes the chloride. Low neuronal chloride is the hallmark of virtually all mature central nervous system neurons. The study findings help us better understand the neurodevelopmental neuronal chloride shift at birth and form a basis for exploring chloride increases in neuronal injury. Researchers may focus on conditions like epilepsy and neuropathic pain to learn whether high chloride levels could be causing problems. The researchers have shown that binding of the REST transcriptional repressor complex to a unique binding element in the promoter portion of the Kcc2b gene works as a transcriptional dual-brake mechanism.  Releasing the REST-complex "brake" leads to increased Kcc2b expression, which "pumps" out the chloride in mature neurons. 


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