This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The long-term goal of the research is to understand the cellular mechanisms underlying epilepsy and to find a better strategy for its treatment. Substance P (SP) is a neuropeptide distributed in both the peripheral and central nervous systems. In vivo experiments show that SP is involved in epilepsy, however, the mechanisms are unknown. Based on the observations that 1) the GABAergic interneurons in hippocampus play a pivotal role in epilepsy, 2) SP receptors are selectively expressed by interneurons and 3) SP enhances both AMPA receptor (AMPAR)-mediated excitatory and GABAA-receptor-mediated inhibitory synaptic transmissions onto interneurons in hippocampal slices (our preliminary data), we propose to test a hypothesis that SP modulates epileptogenesis by regulating the synaptic functions of hippocampal interneurons. Specifically, we intend to address the following issues: (1) Because SP increases AMPA EPSCs by a postsynaptic mechanism, we will determine the extent to which SP increases AMPAR open probability, conductance and/or numbers on postsynaptic membranes at hippocampal interneuron synapses by using peak-scaled non-stationary variance analysis. We will then establish the roles of three downstream signaling pathways (phospholipase C, phospholipase A2 and adenylyl cyclase) of SP receptors in the effects of SP. Finally, we will determine the roles of endogenously released SP in increasing interneuron AMPAR function; (2) Because our results show that SP increases both the frequency and the amplitude of action potential-dependent GABAA receptor-mediated spontaneous IPSCs at interneuron synapses, we will determine the ionic mechanisms by which SP excites interneurons to increase GABA release and the involved signaling pathways of SP receptors; (3) We will determine whether SP increases or decreases seizure activity using a pilocarpine-induced epilepsy model in hippocampal slices and determine the roles of the signaling pathways downstream of SP receptors in seizures. Because SP receptors are exclusively distributed on hippocampal interneurons, our research may help establish a novel approach for treating epilepsy by selectively modulating SP receptor functions on interneurons.
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