Throughout the nervous system, GABAA receptor-mediated inhibition controls neuronal network activity. Within the hippocampus, diverse interneurons that utilize a variety of GABAA receptor subtypes control and coordinate activity in circuits that play crucial roles in learning and memory. These circuits are also susceptible to pathological changes in conditions such as Alzheimer's disease and epilepsy, and the receptors that they utilize are the targets of many clinically used drugs;understanding their organization and function are directly relevant to human health. We propose to test the hypothesis that receptors containing the GABAA receptor a5 and 03 subunits, which are heavily expressed in the dendritic layers of the hippocampal CA1 region, contribute to slow synaptic inhibition, that they are instrumental in controlling responses to repetitive stimulation, and that they participate in the generation or expression of network oscillations. To test these hypotheses we have identified three specific aims: 1) test the contributions of ct5 and (33 subunits to inhibition in hippocampal pyramidal neurons in vitro;2) test the contributions of a5 and (33 subunits to integrative cellular properties and network function in the hippocampus in vitro;and 3) test the contributions of a5 and (33 subunits to hippocampal network oscillations. To accomplish these aims we will follow a combined genetic and pharmacologic approach, using gene-targeted mice and drugs that have intrinsic subunit selectivity or are rendered selective by subunit-specific mutations. The long term-goal of this research is to relate the properties of individual subunits and synapses to activity patterns and network responses that underlie cognitive functions such as learning and memory.
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