Harvard University - Department of Molecular & Cellular Biology

REMOVING AN ENDOGENOUS PROTOTOXIN RESTORES VISION

December 9th, 2010


(L to R) Hirofumi Morishita and Takao K. Hensch

Much of our behavior reflects the neural circuits sculpted by experience during early developmental critical periods. Such heightened brain plasticity declines into adulthood, often limiting recovery of function. On the other hand, the adult brain needs stability. Excessive plasticity can disrupt circuit computations by allowing modification in response to irrelevant information, which may contribute to mental illness. We identified a novel molecular ‘brake’ that normally dampens brain plasticity beyond the critical period. Strikingly, by disrupting this signaling pathway, we could successfully restore vision to mice rendered amblyopic earlier in life. These findings carry a broad impact far beyond neuroscience, including strategies for adult education, recovery from brain injury, and therapeutic interventions for neurodevelopmental disorders.

 

A ‘lazy eye’ or monocular cataract early in life results in an enduring loss of visual acuity (amblyopia) reflecting aberrant circuit remodeling within the primary visual cortex. Amblyopia affects 2-4% of the human population and exhibits little recovery in adulthood. We found that ‘Lynx1’ expression increases in mouse visual cortex only after the critical period. An endogenous prototoxin with a structure similar to a-bungarotoxin in snake venom (Figure), Lynx1 binds nicotinic acetylcholine receptors (nAChR) to promote their desensitization. Removal of Lynx1 enhanced nAChR signaling, in turn resetting excitatory-inhibitory local circuit balance to a permissive state for plasticity. ACh signaling and recovery of function could similarly be enhanced by cholinesterase inhibitors. As these are clinically approved for use in humans, novel translational opportunities can now be pursued.

While a permissive role for ACh has long been appreciated during the critical period, it has remained a mystery why visual plasticity is severely restricted in adulthood. Lynx1 provides a molecular basis for maintaining circuit stability even in the presence of massive cholinergic innervation from the basal forebrain throughout life.

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