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Study finds potential ‘master key’ to brain plasticity

by Eva Voinigescu
Mar 20 / 17

Why is it that even well into adulthood we prefer the music we listened to as young adults? And how is it that children seem to pick up language as if by osmosis while it takes most adults years to reach a base level of fluency in a new tongue?

Scientists have been trying to figure out the mechanisms behind this early-life neuroplasticity – the brain’s ability to change, learn and form new connections between neurons – for decades. Now, a group of researchers including Takao Hensch (Harvard University), a senior fellow in CIFAR’s Child & Brain Development program, have confirmed the role of a homeoprotein called Otx2 in regulating the beginning and end of critical periods of plasticity across multiple parts of the brain.

“This is the first clear piece of evidence that Otx2 is like a master regulator coordinating brain development across brain regions,” said Hensch.

This finding has implications for the future treatment of psychiatric and intellectual disorders like schizophrenia and autism, whose onset might be caused in part by the mistiming of these critical periods.

Published in Molecular Psychiatry last month, the paper builds on two existing discoveries by Hensch and his collaborators. The researchers had previously found that a particular type of neuron called a parvalbumin-positive or PV+ cell is responsible for determining when critical periods of plasticity arise in the brain’s visual system. Furthermore, the accumulation of Otx2 in PV+ cells triggers their developmental timing.

In 2008, Hensch and his team also found that, uncharacteristically for a homeoprotein, Otx2 is produced outside of the PV+ cells which rely upon it for maturing. Instead, Otx2 is attracted by, and binds to, the perineuronal net (PNN), a structure rich in sugar-bearing proteins that PV+ cells enwrap themselves in as they mature.

In the current paper, Hensch and his team used a mouse carrying a mutation in this binding site to test what happens if Otx2 can no longer find its PV+ target. Their results showed that the mutation delays the accumulation of Otx2 in PV+ cells, slowing their maturation and compromising the integrity of the PNN. This caused a delay of critical periods not only in the primary visual cortex as they had expected, but also in the auditory cortex and the medial prefrontal cortex, which processes more complex cognitive behaviours.

Disrupted function of the PV+ circuitry and damage to the PNN have previously been implicated in a variety of psychiatric illnesses, suggesting that Otx2 might have a brain-wide role in establishing mental health. 

For example, in this study, delaying the auditory cortex and medial pre-frontal cortex critical plastic periods allowed anxiety levels to be regulated by music even in the adult mutant mice. Hensch and his team are now testing whether they can re-establish proper PV+ function in other animal models by decreasing or enhancing Otx2 levels.

However, tampering with the timing of critical periods could come at a price. 

“It’s a kind of balancing act between plasticity and stability,” says Hensch. “Perineuronal nets are just one of the half dozen or so factors whose function is actually to block or dampen brain plasticity. From an evolutionary point of view, it seems like a lot of effort to prevent plasticity has been conserved, so you start to wonder, why?”       

The paper suggests mistimed critical periods may have other cognitive consequences aside from mental illness that have yet to be discovered, including implications for the proper development of complex behaviours like language, which requires the sequential interplay and timing of multiple critical periods.

Nevertheless, Hensch’s findings hold promise for possible future therapeutic strategies for treating psychiatric and intellectual disorders. For one, Otx2 is produced in a part of the brain that is accessible to the blood and consequently pharmaceuticals. By combining behavioural therapies with judicious brain plasticity manipulation, Hensch says these therapies might be closer than we think.