Abstracts

A hallmark of post-seizure hippocampus is the loss of somatostatin-containing GABAergic interneurons in the hilus of the dentate gyrus. This neuronal loss can extend into CA1 in some epilepsy models. Previous studies from our laboratory have shown that the neuropeptide somatostatin (SST) has antiepileptic properties in hippocampus, suggesting loss of the SST system may contribute to post-seizure hyperexcitability. We utilized SST receptor knockout mice and subtype-selective agonists to investigate the receptor subtype that mediates SST actions in hippocampus. We made hippocampal slices from C57Bl/6J and SST[sub]2[/sub] and SST[sub]4[/sub] knockout mice, and used intracellular and extracellular recording techniques to examine the action of SST and subtype selective SST agonists on synaptic physiology and plasticity and in vitro seizure models. We used pentylenetetrazole (i.p.) as a chemoconvulsant to examine changes in seizure thresholds and latencies in SST[sub]2[/sub] and SST[sub]4[/sub] knockout mice compared to wildtype. We performed receptor autoradiography with [¹²⁵I]-Tyr⁰-SST to determine the contribution of SST[sub]2[/sub] and SST[sub]4[/sub] to high affinity SST binding in hippocampus. In SST[sub]4[/sub] knockout mice, all high affinity SST binding detectable using autoradiography is lost in CA1. High affinity binding in cortex, amygdala, and the rest of the brain is maintained in SST[sub]4[/sub] knockouts. Likewise, electrophysiological effects of SST in CA1 are much diminished in SST[sub]4[/sub] knockout mice, thus this receptor mediates the majority of SST effects in this region. In contrast, effects of SST in dentate gyrus are maintained in SST[sub]4[/sub] knockout mice, suggesting another receptor, likely SST[sub]2[/sub], mediates SST actions in this hippocampal region. Latencies to different seizure stages evoked by pentylenetetrazole are decreased in SST[sub]4[/sub] but not SST[sub]2[/sub] knockout mice. Our results show SST[sub]4[/sub] is the predominant somatostatin receptor subtype in hippocampus and mediates the majority of SST actions in CA1. Further, mice lacking the SST[sub]4[/sub] receptor subtype have shorter latencies to different seizures stages when challenged with pentylenetetrazole. These results suggest that SST is released during seizures and interacts with SST[sub]4[/sub] to act as an endogenous antiepileptic. Thus the seizure-induced reduction of SST in hippocampus likely contributes to post-seizure hyperexcitability and the development of secondary seizures. SST[sub]4[/sub] receptors could therefore be important novel targets for new antiepileptic and antiepileptogenic drugs. (Supported by NIH grants NS 38633 (MKT) and MH 58543 (LdL) and an EFA predoctoral fellowship (CQ).)