Compensatory changes in the hippocampus of somatostatin knockout mice: upregulation of somatostatin receptor 2 and its function in the control of bursting activity and synaptic transmission

Somatostatin-14 (SRIF) co-localizes with gamma-aminobutyric acid (GABA) in the hippocampus and regulates neuronal excitability. A role of SRIF in the control of seizures has been proposed, although its exact contribution requires some clarification. In particular, SRIF knockout (KO) mice do not exhibit spontaneous seizures, indicating that compensatory changes may occur in KO. In the KO hippocampus, we examined whether specific SRIF receptors and/or the cognate peptide cortistatin-14 (CST) compensate for the absence of SRIF. We found increased levels of both sst(2) receptors (sst(2)) and CST, and we explored the functional consequences of sst(2) compensation on bursting activity and synaptic responses in hippocampal slices. Bursting was decreased by SRIF in wild-type (WT) mice, but it was not affected by either CST or sst(2) agonist and antagonist. sst(4) agonist increased bursting frequency in either WT or KO. In WT, but not in KO, its effects were blocked by agonizing or antagonizing sst(2), suggesting that sst(2) and sst(4) are functionally coupled in the WT hippocampus. Bursting was reduced in KO as compared with WT and was increased upon application of sst(2) antagonist, while SRIF, CST and sst(2) agonist had no effect. At the synaptic level, we observed that in WT, SRIF decreased excitatory postsynaptic potentials which were, in contrast, increased by sst(2) antagonist in KO. We conclude that sst(2) compensates for SRIF absence and that its upregulation is responsible for reduced bursting and decreased excitatory transmission in KO mice. We suggest that a critical density of sst(2) is needed to control hippocampal activity.