The development of vision in children and other young mammals involves a critical period when synaptic connectivity in the visual cortex can be altered by visual experience. As the brain matures synaptic plasticity diminishes, leaving the visual connections in a more stable state. The loss of plasticity limits the brain's capacity for further adaptation or recovery from injury. The discovery of methods for extending or reinstating synaptic plasticity would have profound therapeutic implications. We and others hypothesize that plasticity is regulated by a type of glutamate receptor called the NMDA receptor. NMDA receptors exist in a number of molecular forms determined by alternative subunit composition and alternative splicing of mRNA. Two recent findings suggest the hypothesis that changes in the composition and resultant physiological properties of NMDA receptors are responsible for developmental changes in plasticity. First, experiments in recombinant systems have shown that physiological responses to glutamate vary with receptor composition. Second, receptor composition changes during cortical development. After testing the relations between receptor composition, physiology and plasticity in visual cortex, we will ask whether these relationships are more than correlative by manipulating the plastic and testing for linked changes in NMDA receptor development. In the first experiments we will examine the development of receptor composition using in situ hybridization and immunohistochemistry. Second we will use whole cell recording, followed by PCR or immunohistochemistry, to ask whether, on a cell by cell basis, the relation between receptor composition and receptor physiology in real neurons is similar to that already known in recombinant systems. Third, having defined correlations between NMDA receptor composition, physiology, and visual plasticity, we will use dark rearing, intraocular tetrodotoxin and drug treatment (MK-801) to perturb the plastic period and/or receptor development. We will then ask whether the changes in development of receptor composition and physiology occur in synchrony with changes in plasticity. Finding that the effects of these perturbation are synchronous will greatly strengthen the hypothesis that synaptic plasticity in the visual cortex is controlled by NMDA receptors.
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