Somatostatin receptors differentially affect spontaneous epileptiform activity in mouse hippocampal slices

Somatostatin‐14 [somatotropin release‐inhibiting factor (SRIF)] reduces hippocampal epileptiform activity but the contribution of its specific receptors (sst 1−5 ) is poorly understood. We have focused on the role of sst 1 and sst 2 in mediating SRIF modulation of epilepsy using hippocampal slices of wild‐type (WT) and sst 1 or sst 2 knockout (KO) mice. Recordings of epileptiform discharge induced by Mg 2+ ‐free medium with 4‐aminopyridine were performed from the CA3 region before and after the application of SRIF compounds. In WT mice, SRIF and the sst 1 agonist CH‐275 reduce epilepsy whereas sst 1 blockade with its antagonist SRA‐880 increases the bursting discharge. Activation of sst 2 does not affect the bursting frequency unless its agonist octreotide is applied with SRA‐880, indicating that sst 1 masks sst 2 ‐mediated modulation of epilepsy. In sst 1 KO mice: (i) the bursting frequency is lower than in WT; (ii) SRIF, CH‐275 and SRA‐880 are ineffective on epilepsy and (iii) octreotide is also devoid of effects, whereas blockade of sst 2 with the antagonist d ‐Tyr 8 Cyn 154806 increases the bursting frequency. In sst 2 KO mice, the SRIF ligand effects are similar to those in WT. In the whole hippocampus of sst 1 KO mice, sst 2 mRNA, protein and binding are higher than in WT and reverse transcription‐polymerase chain reaction of the CA3 subarea confirms an increase of the sst 2 messenger. We conclude that sst 1 mediates inhibitory actions of SRIF and that interactions between sst 1 and sst 2 may prevent sst 2 modulation of epilepsy. We suggest that, in sst 1 KO mice, activation of over‐expressed sst 2 reduces the bursting frequency, indicating that sst 2 density represents the rate‐limiting factor for sst 2 ‐mediated modulation of epilepsy.