Neuropharmacology 2015-12-01

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

Sarah J Lucas, David L Armstrong

Index: Neuropharmacology 99 , 232-41, (2015)

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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.Published by Elsevier Ltd.