Excitatory amino acid (EAA) receptors form part of a major neurotransmitter system in the brain that contributes to synapse formation, learning and memory and the pathogenesis of neurological disorders. Recent developments in molecular cloning of EAA receptors have revealed an impressive heterogeneity of molecular forms of EAA receptors. At the same time, we have produced evidence that in hippocampal hilar neurons two distinct populations of excitatory synapses can be found in relation to specific anatomical correlates. We propose to test the hypotheses that postsynaptic spines and the EAA receptor subunits composing postsynaptic receptor-channel complexes play a major role at these synapses as determinants of synaptic strength. EAA-mediated synapses in visually identified neurons that differ in the presence or the absence of postsynaptic spines will be analyzed using whole-cell voltage-clamp recordings of synaptic currents. We will determine the subunit composition of postsynaptic receptors in hilar neurons by combined immunocytochemical techniques and EAA-activated single channel current recordings in native membrane outside-out patches compared to recombinant receptors. Biochemical as well as physiological stimulation will be used to test the hypotheses that structural modifications of postsynaptic spines or of EAA receptors will produce changes of synaptic efficacy in hilar neurons. We also propose to study long-term changes of excitatory synapses during normal and experimentally modified visual experience in spiny and aspiny neurons of rat primary visual cortex. Finally, in light of experimental evidence for a role of neurotrophic factors underlying the plasticity of synaptic connections during development of the visual system, we will study the effects of endogenously provided neurotrophins on EAA-mediated synapses during normal development and during visual deprivation. Data obtained from these specific aims will permit the relative contributions of postsynaptic spines and variation in the molecular forms of excitatory amino acid receptors to be distinguished as determinants of synaptic functions that underlie behavior and that are relevant in various CNS disorders.
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