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

Abstract

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 sst2 receptors (sst2) and CST, and we explored the functional consequences of sst2 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 sst2 agonist and antagonist. sst4 agonist increased bursting frequency in either WT or KO. In WT, but not in KO, its effects were blocked by agonizing or antagonizing sst2, suggesting that sst2 and sst4 are functionally coupled in the WT hippocampus. Bursting was reduced in KO as compared with WT and was increased upon application of sst2 antagonist, while SRIF, CST and sst2 agonist had no effect. At the synaptic level, we observed that in WT, SRIF decreased excitatory postsynaptic potentials which were, in contrast, increased by sst2 antagonist in KO. We conclude that sst2 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 sst2 is needed to control hippocampal activity.

Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity

“…In turn, our finding of decreased LTP in CA1 upon somatostatin deficiency seems at odds with previous observations of an increase in basal synaptic transmission and shortterm plasticity, but unaltered LTP, after sst2 gene invalidation (Dutar et al 2002). It should be kept in mind, however, that multiple somatostatin receptors are expressed in the hippocampus, and that compensatory changes may occur after invalidation of the somatostatin gene (Cammalleri et al 2006) and possibly also the sst2 gene. The combination of genetic and pharmacological experiments, however, enabled us to control for such compensations, and to investigate the net effect of somatostatin on hippocampal plasticity, critical for our behavioral findings.…”

Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages

“…Among synthetic ligands, we used the peptidyl multiligand analog SOM230, which binds with high affinity to sst 1,2,3,5 [42][43][44], and the peptidyl multiligand analog KE108, which binds with high affinity to all five SRIF receptors [44,45]. The sst 1 -selective peptidyl agonist CH-275 [35,41,46,47], the sst 2 -preferring peptiydyl agonist SMS 201-995 (also known as sandostatin or octreotide) [38,41,46,48,49], and the sst 2 -selective nonpeptidyl agonist L-779,976 [46, 49 -51] were also used in the absence or presence of the sst 1 -selective nonpeptydil antagonist SRA-880 [46,52,53] and the sst 2 -selective peptydil antagonist CYN [36,38,48,49,54]. All compounds were applied at 1 M, which from previous studies, is a concentration giving maximal re- ceptor occupancy [2,41].…”

“…Using published protocols [35,36], the cells were fixed in 4% paraformaldehyde for 10 min at room temperature before washing with 0.1 M PB. The polyclonal antibodies directed against sst 1 and the sst 2A isoform of sst 2 [37,38] were diluted 1:100 in PB containing 0.1% Triton X-100 overnight at 4°C. Cells were then washed in PB and incubated in the presence of the appropriate secondary antibodies conjugated with Alexa Fluor 488 fluorescent dyes at a dilution of 1:200 in PB containing 0.1% Triton X-100 for 1 h at room temperature.…”

Somatostatin and Cognitive Function in Neurodegenerative Disorders

“…One study reported an intracellular Ca 2+ -dependent modulation of AMPA currents postsynaptically, mediated by sst2 activation in the hypothalamus [46]. Interestingly, in sst2 knock-out (KO) mice, the glutamatergic responses were increased in the hippocampal slices [47], suggesting that SST exerts an inhibitory tone on glutamatergic transmission through sst2 activation [48]. However, the activation of sst4, selectively expressed in the hippocampal CA1, increased the hippocampal glutamatergic responses, an effect inhibited by the activation of sst2, suggesting the possible functional interaction of these subtypes [49].…”