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 Mg2+-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.