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Neuropharmacology

Protein phosphatase modulation of somatostatin receptor signaling in the mouse hippocampus.


PMID 26196943

Abstract

Many inhibitory interneurones in the hippocampus release the neuropeptide somatostatin (SST) which inhibits neuronal excitability through Gi/Go-coupled receptors. To investigate the signaling pathways underlying the SST inhibition of neuronal excitability in the hippocampus, we performed perforated patch-clamp recordings from CA1 pyramidal neurones in acute brain slices from P14-P18 mice. Bath application of 1 μM SST reversibly reduces the frequency of action potential firing in response to depolarising current steps, and is associated with neuronal hyperpolarisation and a reduction in membrane resistance. This effect is mediated by potassium channels with KCNK-like pharmacology. In addition, in slices that have been cultured in vitro for seven days or more, SST also produces a hyperpolarisation independent reduction in action potential firing, which can be also observed in acute slices when the Ser/Thr protein phosphatases PP2A and PP4 are inhibited selectively with fostriecin. This hyperpolarisation independent effect of SST appears to be mediated by G-protein-activated inwardly rectifying K+ (GIRK) channels. Knockdown of protein phosphatase 5, by Cre recombinase mediated deletion of the floxed Ppp5c gene, blocks the hyperpolarisation independent effect of SST, and reduces the hyperpolarisation dependent effect in a manner consistent with increased SST receptor desensitisation. Thus, reversible protein phosphorylation provides a mechanism to enhance or diminish the inhibitory effect of SST, which could allow system level regulation of circuit excitability in the hippocampus.