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

The K⁺ 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 hippocampal CA1 pyramidal 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 SST ₄ 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.