Recovery from amblyopia in the adult mouse through dark exposure, light reintroduction and perisynaptic proteolysis.

An imbalance in the quality of visual input across the two eyes during development induces amblyopia, a disorder affecting up to 6% of the world's population. In animal models, severe deprivation amblyopia can be induced by early-onset, chronic monocular occlusion, and is manifest as a loss of spatial acuity through the deprived eye and a decrease in the strength of neuronal responses evoked by deprived eye stimulation. In all species, amblyopia is highly resistant to reversal in adulthood, due in part to the decline in synaptic plasticity in the primary visual cortex with age. However, we have previously demonstrated that visual deprivation (dark exposure) followed by light reintroduction (LRx) rejuvenates plasticity in the adult amblyopic cortex. The reactivation of plasticity triggered by DE/LRx is mediated by an increase in the activity of a matrix metalloproteinase (MMP9), that is perisynaptic, specific to thalamocortical synapses, and results in degradation of trans-synaptic adhesion proteins. Furthermore, live imaging of MMP activity in the mouse visual cortex demonstrates that DE lowers the threshold for MMP activation, enabling weak visual input through the amblyopic pathway to engage perisynaptic proteolysis. In amblyopic adult mice, the reactivation of synaptic plasticity by this novel and dynamic signaling pathway can be harnessed to promote full recovery of visually-evoked neuronal responses and spatial acuity.