Project Summary The decline in synaptic plasticity with age is thought to impose severe constraints on the recovery from amblyopia in adults. Although this developmental loss was previously thought to be irreversible, our previous work established that robust plasticity can be reactivated in the adult visual cortex by dark exposure (DE) followed by light reintroduction (LRx). We outline a series of experiments to delineate the cellular and molecular mechanisms that couple DE/LRx to the rejuvenation of synaptic plasticity in the adult visual system. We propose that DE induces homeostatic changes in the composition of synaptic NMDARs in the primary visual cortex, which lowers the threshold for Hebbian plasticity. However, the response to DE over- compensates for the loss of visual input and results in neuronal hyper-excitability. The threshold for activation of perisynaptic proteolysis by LRx at thalamocortical synapses is also lowered by DE. The response to LRx reduces feed-forward excitation to the cortex and is mediated by rapid plasticity of presynaptic function.