Somatostatin receptor subtype 4 couples to the m-current to regulate seizures

TheK(+) M- current (I-M, Kv7) is an important regulator of cortical excitability, and mutations in these channels cause a seizure disorder in humans. The neuropeptide somatostatin ( SST), which has antiepileptic properties, augments I-M in hippocampalCA1pyramidal neurons. We used SST receptor knock- out mice and subtype- selective ligands to investigate the receptor subtype that couples to I-M and mediates the antiepileptic effects of SST. Using pentylenetetrazole as a chemoconvulsant, SST2, SST3, and SST4 receptor knock- out mice all had shorter latencies to different seizure stages and increased seizure severity when compared with wild- type mice. However, the most robust differences were observed in the SST4 knock- outs. When seizures were induced by systemic injection of kainate, only SST4 knock- outs showed an increase in seizure sensitivity. We next examined the action of SST and subtype- selective SST agonists on electrophysiological parameters in hippocampal slices of wild- type and receptor knock- out mice. SST2 and SST4 appear to mediate the majority of SST inhibition of epileptiform activity in CA1. SST lacked presynaptic effects in mouse CA1, in contrast to our previous findings in rat. SST increased I-M in CA1 pyramidal neurons of wild- type and SST2 knock- out mice, but not SST4 knock- out mice. Using M- channel blockers, we found that SST4 coupling to M- channels is critical to its inhibition of epileptiform activity. This is the first demonstration of an endogenous enhancer of I-M that is important in controlling seizure activity. SST4 receptors could therefore be an important novel target for developing new antiepileptic and antiepileptogenic drugs.