Degradation of the visual characterized by a decrease of visual acuity that cannot be improved by corrective lenses. Amblyopia is relatively common in the general population and constitutes a major cause of visual disability. In this condition, connections relaying information from the deprived eye to the visual cortex withdraw and connections relaying information from the experienced eye expand, with most cortical neurons responding only to stimulation of the experienced eye. As a consequence, visual function mediated by the deprived eye can be completely and irreversibly lost. Recovery of binocular function can be obtained, however, if normal visual stimulation to the deprived eye is restored promptly after deprivation has been initiated. In view of the substantial scientific and clinical relevance of these types of neural plasticity, there is an urgent need to elucidate the underlying cellular and molecular mechanisms. Neurophysiological activity involving the N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be required for the loss of connections from the deprived eye. The prevailing hypothesis is that the voltage-dependent magnesium blockade of the NMDA receptor enables it to act as a correlation detector. Inputs from the non-deprived eye that can drive correlated pre-and post-synaptic activity are strengthened, while synaptic inputs from the deprived eye that exhibit uncorrelated firing with the post-synaptic cell are lost. In addition, calcium influx through the NMDA receptor associated channel regulates intracellular kinases that activate the transcription factor cAMP/Calcium-dependent response element binding protein (CREB). Although this cascade of events has provided a framework for understanding the mechanisms of cortical plasticity, several important questions have remained unanswered concerning the role of NMDA receptors and CREB in ocular dominance plasticity: I) do NMDA receptors function as correlation detectors in ocular dominance plasticity? ii) is activation of CREB required for the loss of cortical binocularity during monocular deprivation?, iii) do NMDA receptors have a function in recovery of cortical binocularity following re-establishment of visual stimulation to the deprived eye?, and iv) what function does CREB have in recovery of cortical binocularity? The proposed studies will use molecular-genetic manipulations to answer these important questions. Antisense reagents will be used to reduce expression of individual genes, and viral mediated gene transfer will be used to induce overexpression of individual genes or expression of mutated genes in the visual cortex. Use of these complementary techniques will provide a new and exciting opportunity to examine the molecular mechanisms of loss and recovery of visual cortical function. Collectively the results of the proposed studies will place us in a position to start tracing the sequence of molecular events leading to loss and recovery of cortical function in monocular deprivation amblyopia. A better understanding of these mechanisms should provide specific targets to develop novel therapeutic approaches in the treatment of amblyopia.
