The long-term objective of the proposed studies is to further characterize the properties of glutamate receptors in the mammalian neocortex. These studies will increase our understanding of excitatory synaptic transmission in higher cortical structures and the control of excitability in central neurons. Patch clamp recordings from visually identified cells in slices of neocortex maintained in vitro will be used to assess the role of glutamate inotropic and metabotropic receptors (mGluRs) in regulating synaptic excitation. Biophysical studies will focus on interneurons in layer 1 to determine how glutamate receptors regulate activity in local cortical circuits. The overall goal is to better understand the role of glutamate as a neurotransmitter and novel neuromodulator in the neocortex. Proposed studies will examine the pharmacological properties of a novel EPSP observed in the presence of high concentrations of NMDA and non-NMDA receptor antagonists. It is hypothesized that this response results from activation of G-protein coupled mGluRs. The ability of mGluR antagonists and/or intracellular GDP-beta-S to block this response will be determined. Additional studies will determine if Ca2+ -permeable AMPA-receptors mediate EPSCs in identified interneurons in rat neocortex. EPSCs will be examined for rectification in I-V relations and Ca2+ permeability will be determined from reversal potential shifts measured in solutions with differing extracellular Ca2+ concentrations. Comparison will be made with whole cell responses to bath applied kainic acid, a non-desensitizing activator of AMPA receptors. In further studies, the ability of mGluR agonists to modulate EPSCs and IPSCs in identified interneurons will be examined. Despite their marked expression in the neocortex, the role of mGluRs in normal synaptic transmission in this brain region is unclear. The goal of the proposed studies is to examine the effects of mGluR activation on excitability of identified interneurons in rat neocortex and determine the mechanisms underlying these actions. It is hypothesized that terminals making synapses on layer I interneurons express different classes of mGluRs, resulting in unique responses to mGluR agonists. The direct postsynaptic response of interneurons to activation of mGluRs will be studied in neocortical interneurons under whole-cell voltage clamp conditions. it is hypothesized that certain classes of layer I cells express mGluRs coupled to IP3 formation resulting in intrinsic membrane oscillations in response to mGluR agonists. Higher nervous functions, including learning and memory acquisition, are believe to involve glutamate mediated synaptic transmission. Neurological diseases such as epilepsy, stroke and neurodegenerative disorders may result from altered glutamate receptor functioning or overstimulation. The proposed studies will increase our understanding of the role of glutamate as a neurotransmitter and provide a better understanding of cortical excitability under normal and pathophysiological conditions.
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