The primary objective is the investigation of excitatory neurotransmission in the hippocampus. Quantitative neurophysiological methods will be employed to study the response of pyramidal neurons in the CA3 and CA1 subregions to exogenously and endogenously (i.e., synaptically released) applied excitatory amino acids. In vitro hippocampal slices, organotypic hippocampal explant cultures, and acutely isolated pyramidal cells will be used as model systems. The former preparation will be employed in continuing studies using the single-electrode voltage-clamp technique, of (1) the mechanism of action of iontophoretically applied excitatory amino acids, (2) the effects of bath application of selected antagonists, and (3) the role of magnesium in controlling synaptic excitability. Organotypic explant cultures and isolated cells will be used to examine the properties of single glutamate channels in hippocampal neurons using patch-clamp techniques. Quantitative studies of antagonist effects will determine the nature of the amino acid receptor mediating synaptic excitation in the CA1 and CA3 subfields of the hippocampus. The patch-clamp studies will provide insights into the gating mechanisms underlying excitatory synaptic transmission that cannot be obtained by other methods. The proposed studies will advance our understanding of the role played by excitatory amino acid receptors in synaptic transmission in the mammalian cortex. Alterations in such receptors have been implicated in the induction and regulation of long-term potentiation (a type of synaptic plasticity) in the hippocampus. Furthermore, certain glutamate antagonists have been shown to have anticonvulsant properties, a finding of particular significance because of the high seizure susceptibility of the hippocampus. The quantitative information derived from the proposed studies will provide a firm basis for subsequent investigations of the role of excitatory amino acid receptors in synaptic plasticity, learning, and disease processes such as epilepsy.
Showing the most recent 10 out of 43 publications
