The sequential expression of the genes coding for NR2 subunits of N-methyI-D-aspartic acid receptors (NMDARs) during development produces an elegant concert of events that result in the expression of NMDA channels tailored in their kinetic properties to the physiologic roles they play. In this competitive renewal, we propose to continue the study of heterogeneity in excitatory synapses by electrophysiology, molecular biology and anatomic techniques. Our past studies demonstrate a selective regulation of NMDAR subtypes that control the functional properties of cerebellar synapses. Based on these results, we will investigate the consequences of the diversity of synaptic and extrasynaptic NMDARs in cerebellar granule cells (CGCs) for excitatory synaptic transmission and the control of information flow in the cerebellar cortex. CGCs offer the unique possibility to perform high-resolution patch clamp recordings of NMDAR-mediated synaptic currents with resolution of single-channel currents. Long-term potentiation (LTP) and long-term depression (LTD) and the occurrence of tonic NMDA conductances will be studied in cerebellar slices from wild-type mice and mice lacking NMDAR subunits. Combined electrophysiology and electron microscopy will allow quantitation of the relative role of NMDAR subtypes in producing synaptic and extrasynaptic responses. Furthermore, cultured CGCs are a system of homogenous neurons in which to selectively overexpress or delete proteins and obtain data on how these changes regulate synaptic transmission. These approaches will allow us to test our leading hypothesis that the heterogeneity of molecular forms of NMDARs at excitatory synapse has physiological roles in determining the efficacy of excitatory synaptic transmission and, in turn, cerebellar plasticity. The results of these studies will fill a gap in our knowledge of what these physiologic roles are and how they shape excitatory synaptic transmission. Using cerebellar synapses from subunit null mice we will have a unique opportunity to answer a fundamental question: Why do we need distinct subtypes of a protein key to the plasticity of the central nervous system? Transgenic mice with alteration of the expression of NMDAR subunits are becoming exciting models of human disorders ranging from epilepsy to schizophrenia. Thus, the results we will derive, although clearly related to basic neuroscience, will have notable applications to neurological disorders and to mental health ? ?
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