The long-range objectives of this application are to determine the physiological effects, mechanisms of action and neuronal function of the family of prosomatostatin-derived and related peptides (SSTs and cortistatin). Despite decades of research, the function of SST in extrahypothalamic brain remains unknown. The new studies we plan are based on our findings that: 1) SSTs hyperpolarize CA1 hippocampal neurons (HPNs) by augmenting two K+ conductances: the M-current (Im) and the leak current (Ilk); muscarinic agonists block both these currents; 2) arachidonic acid (AA) metabolites mediate these SST K+ channel effects; 3) SST reduces excitatory (but not inhibitory) postsynaptic currents (EPSCs), and especially polysynaptic or hyperexcitable neurotransmission, in both CA1 and CA3 hippocampal pyramidal neurons (HPNs); 4) cortical regions contain a novel SST-like peptide, cortistatin (CST), resulting from a different gene but exerting hippocampal effects qualitatively similar to those of SST. We hypothesize from these findings that these two 'statin' systems function in a concerted way (perhaps with GABA, with which they are often co-localized) as a 'brake' to reduce excitability in the hyperexcitable or epileptic hippocampus. Therefore, the specific aims of this renewal application are to: 1) Continue studies to determine whether the synaptic effects of SST and CST on EPSCs are exerted pre- or postsynaptically; 2) Examine the effects of CST, in both CA1 and dentate, on synaptic plasticity (STP, LTP and LTD) and 3) on the hyperexcitability and epileptiform activity produced by superfusion of bicuculline or low Mg++ concentrations; 4) Begin comparative studies of membrane and synaptic properties, and their responses to SST and CST receptor agonists, in HPNs of several murine genetic models, including those containing knockouts (null mutations) for the CST and SST peptides and for SST receptors, and those overexpressing neuronal CST. Bigenic crosses of these knockouts and CST overexpression will also be studied. These models will allow tests of several hypotheses on the function of CST and SST in brain, including the idea that endogenous CST and SST combine to reduce or prevent feedforward synaptic hyperexcitability and epileptiform activity in hippocampus. To achieve these aims, intracellular and whole-cell voltage-clamp ('patch-slice') neuronal recording will be applied to in vitro slice preparations of hippocampus. CST, SST and other drugs will be applied by superfusion or locally from pipettes. We believe these studies will help to clarify the sites and mechanisms of action of the endogenous SST and CST peptides and their possible role in hyperexcitability and learning and memory, and will help to characterize possible CST- or SST-related dysfunctions in certain disease states such as epilepsy and Alzheimer's dementia.
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