Dissecting the role of aggrecan and perineuronal nets in visual plasticity

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Summary Critical periods are time windows during development when experience-dependent plasticity is most robust. The developing visual system in the premier model for studying how circuits modified by experience-dependent plasticity are consolidated when a critical period closes. This model is clinically relevant because the closure of the visual critical period is implicated in the pathophysiology of amblyopia, a childhood visual disorder characterized by deficits in spatial vision including poor visual acuity and impaired depth perception. Effective therapy is more difficult after the critical period closes because the brain is less plastic. In animal models of amblyopia, monocular deprivation (MD) causes lasting deficits in ocular dominance (OD), binocular depth perception, and visual acuity. The closure of the critical period is coincident with the maturation of perineuronal nets in visual cortex, but how these extracellular structures may limit plasticity is not understood. In the proposed research, we will determine the role and cellular source of aggrecan, a principal component of perineuronal nets, in closing the developmental critical period for plasticity in visual circuits. Our hypothesis is that aggrecan operates outside of perineuronal nets to close the critical period. We will use a combination of behavioral assays of vision, multi-unit electrophysiology, calcium imaging in vivo, and slice electrophysiology in vitro, and genetic manipulations to determine how aggrecan regulates the plasticity of visual circuits. This project will improve understanding of the mechanisms by which experience-dependent plasticity is restricted in the maturing brain and may reveal new avenues for developing therapeutic approaches to treat developmental visual disorders such as amblyopia and central visual impairment.