Scientific Understanding of Consciousness
Amblyopia and Brain Cortical Plasticity
Science 26 November 2010: Vol. 330 no. 6008 pp. 1238-1240
Lynx1, a Cholinergic Brake, Limits Plasticity in Adult Visual Cortex
Hirofumi Morishita1, Julie M. Miwa2, Nathaniel Heintz3 and Takao K. Hensch4
1FM Kirby Neurobiology Center, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
2Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
3Howard Hughes Medical Institute Laboratory of Molecular Biology, Rockefeller University, New York, NY 10065, USA.
4Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
Experience-dependent brain plasticity typically declines after an early critical period during which circuits are established. Loss of plasticity with closure of the critical period limits improvement of function in adulthood, but the mechanisms that change the brain’s plasticity remain poorly understood. Here, we identified an increase in expression of Lynx1 protein in mice that prevented plasticity in the primary visual cortex late in life. Removal of this molecular brake enhanced nicotinic acetylcholine receptor signaling. Lynx1 expression thus maintains stability of mature cortical networks in the presence of cholinergic innervation. The results suggest that modulating the balance between excitatory and inhibitory circuits reactivates visual plasticity and may present a therapeutic target.
The waxing and waning of cortical plasticity during a postnatal critical period serves to consolidate neural circuits and behavior, but in turn limits recovery of function in the adult brain. For example, discordant vision through the two eyes during an early critical period results in the enduring loss of visual acuity (amblyopia) that reflects aberrant circuit remodeling within primary visual cortex (V1). Amblyopia, which affects 2 to 4% of the human population, exhibits little recovery in adulthood. Identifying specific biological mechanisms that restrict adult plasticity would inspire potentially novel strategies for therapy.
Lynx1 expression increases only after the critical period for amblyopia in adult V1 both at the protein and mRNA level. Along the visual pathway, Lynx1 transcripts were expressed both in V1 and the lateral geniculate nucleus (LGN). In contrast, expression of another member of the lynx family, Lynx2, declined over the critical period and was hardly found in the visual pathway. We therefore directly assessed Lynx1 function in the binocular region by electrophysiological recordings from knockout mice.
Taken together, Lynx1 provides both a valuable endogenous tool with which to probe critical-period closure and offers novel therapeutic and conceptual insight. In contrast to muscarinic receptors engaged during the critical period, our results highlight a nicotinic component for adult V1 plasticity. Although we do not rule out a role for muscarinic receptors, deletion of Lynx1 alone is sufficient to rescue visual acuity. Recovery strategies aimed at the Lynx1-nAChR interaction could be fruitful in conjunction with attentional tasks that stimulate cholinergic release (e.g., perceptual learning, video-game training). Clinically approved cholinesterase inhibitors that boost the afferent response in human visual cortex may be useful for treating some amblyopes, including those with subcortical changes. Amblyopia might further serve as a diagnostic measure to identify tobacco exposure or schizophrenia.
Although a permissive role for cholinergic input has long been appreciated during the critical period, it has remained a mystery why V1 plasticity is severely restricted in adulthood even in the presence of massive innervation from the basal forebrain. Lynx1 expression not only contributes to nAChR agonist binding and desensitization kinetics, but also may respond to changes in network activity. Local regulation of Lynx1 levels may allow cholinergic activation to induce islands of plasticity while maintaining overall circuit stability. Visual attention tasks in fact preferentially modulate fast-spiking inhibitory neurons, consistent with a convergence of top-down influences upon local excitatory-inhibitory circuit balance.
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