Experience-dependent modification of excitatory and inhibitory plasticity mechanisms in visual cortex

The immature brain is not simply a small adult brain, and normal development involves a complex series of interactions between nature and nurture. For the visual system, normal development is dependent upon visual experience. Occluding one eye of visual experience early in life (Monocular Deprivation) leads to anatomical and physiological changes in the central visual pathways that leave the deprived eye with poor vision. This has become the best model for studying the most common developmental visual disorder---lazy-eye (amblyopia). Several neural plasticity mechanisms play essential roles in mediating the development of the neural circuits that underlie visual function. In particular, the major excitatory (NMDA, AMPA) and inhibitory receptors (GABAA) play key roles in synaptic plasticity and the emergence of mature anatomical and physiological properties in the visual system. Recent studies, however, have shown that some of these plasticity mechanisms can be affected by abnormal visual experience. This raises the possibility that the balance of these plasticity mechanisms may be affected by visual experience and in turn, may affect the potential for functional recovery from amblyopia. To address these questions, I initiated a comprehensive series of studies to examine experience-dependent changes in the excitatory and inhibitory mechanisms involved in developmental synaptic plasticity. Using quantitative Western blotting, I examined expression of the major excitatory (NR1, NR2A, NR2B, G1uR2), and inhibitory (GABAAalpha1, GABAAalpha3) receptor subunits in visual cortex with normal development (human and kitten), abnormal visual experience (monocular deprivation - kittens), and following rearing regimens designed to promote visual recovery (kittens). In normal development, there is a gradual increase in the expression of NMDA, AMPA, and GABAA receptors that parallels the emergence of functional plasticity in visual cortex. This development is very prolonged in human visual cortex extending well into later childhood. Monocular deprivation leads to significant changes in the balance between these excitatory and inhibitory plasticity mechanisms, and the changes are not uniform across the visual cortex. The portion of visual cortex where the central visual field is represented is most affected. Optimal recovery of plasticity mechanisms following monocular deprivation is promoted by binocular vision, suggesting that good recovery depends upon both binocularly correlated activity and a sufficient level of visually driven activity. Finally, I implemented a novel neuroinformatics approach (Singular Value Decomposition) to quantify the complex multidimensional changes in the global expression pattern of key plasticity mechanisms. This analysis revealed that monocular deprivation leads to a deviation from the normal developmental trajectory but that a short period of binocular vision is sufficient to shift the trajectory back towards the normal direction. The results of these experiments show that there is a delicate balance between excitatory and inhibitory plasticity mechanisms during normal development, and that this balance is dependent upon visual experience.