The mammalian visual system requires experience to develop normally. Lack of sensory experience due to degradation of the visual input of one eye during development may lead to irreversible loss of visual function mediated by this eye. This condition, known as amblyopia, is a major cause of visual disability in children. There is no doubt regarding the substantial scientific and clinical relevance of this type of neural plasticity. However, the cellular and molecular mechanisms underlying this crucial developmental process remain unknown. In recent years much attention has been focused on the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor because of its proposed role in brain development, learning and memory. Its specific role in visual plasticity has, nevertheless, remained elusive. Recent molecular studies have provided an exciting new opportunity to examine the contribution of the NMDA receptor to visual function and plasticity. These studies have shown that this receptor is composed of different subunit proteins and that different combinations of subunits exhibit distinct functional properties. It is proposed here that developmental changes in subunit composition of the NMDA receptor play a critical role in visual plasticity. A novel approach is proposed to examine this hypothesis. Intracortical infusion of antisense DNA will be used to suppress selected NMDA receptor subunits. The receptors should then be assembled from the remaining subunits. The resultant modifications in functional properties of cortical NMDA receptors will be examined by intracellular recordings in cortical slices maintained living in vitro and the changes in visual responses will be assessed in normal animals as well as in those which were monocularly deprived of vision during antisense treatment. This approach offers several significant advantages over currently used pharmacological procedures, such as the possibility of selectively manipulating individual subunits. Moreover, transgenic animals cannot be used to conduct these experiments, since animals lacking some NMDA receptor subunits are not viable. The results should delineate links between the molecular composition of the NMDA receptor and its functional role in visual cortex. In addition, since molecular interventions may one day be used for therapeutic purposes in visual disorders, these studies may provide a new dimension to our clinical armamentarium at the level of the synapse.
