The objective of this study is to determine the actions and mechanisms of the peptide somatostatin (SST) in normal and epileptic neurotransmission. SST has long been speculated to play a role in epilepsy, however its function is unknown. Our planned studies are based on the following: 1) We have shown that SST strongly reduces epileptiform activity in both CA1 and CA3 regions of hippocampus. SST acts on both evoked and spontaneous epileptiform events, suggesting that this peptide may act to limit the spread of seizures through the hippocampus and to other limbic structures. 2) SST appears to specifically reduce recurrent excitatory feedforward neurotransmission which is critical to the generation of epileptiform events. Recurrent excitatory synapses are increased in epileptic tissue. 3) One of the most consistent findings in eplieptic hippocampus is the selective loss of SST-containing neurons in the hilus of the dentate gyrus. The functional consequence of this loss is unknown, nor has the action of SST in the dentate been characterized. 4) Transgenic mice have been developed with null mutations ( knockouts ) for the SST peptide gene or for selective SST receptor subtype genes. These mice provide a unique tool for studying the function of endogenous SST in the brain. Our preliminary data suggests SST has inhibitory actions in the dentate. Therefore the specific aims of this proposal are: 1) Examine the effects of SST on neurotransmission in the dentate, which acts as a gate through which seizure events enter the hippocampus. 2) Examine the effects of SST in hippocampus which has undergone the synaptic remodeling characteristic of epileptic tissue. 3) Begin studies to examine hyperexcitabilty and SST effects in SST or SST receptor knockout mice. We will perform these studies using intracellular, extracellular, and whole-cell patch clamp techniques. These studies will help determine the function of SST in normal and epileptic brain, and could have therapeutic implications in the treatment of epilepsy and other neurological disorders.
