title: Protein phosphatase modulation of somatostatin receptor signaling in the mouse hippocampus.
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.
authors.affiliation: Lab. Neurobiology, National Institute of Environmental Health Sciences, NIH, Durham, NC, 27709, USA. Electronic address: Sarah.Lucas@cantab.net.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lucas
authors.affiliation: Lab. Neurobiology, National Institute of Environmental Health Sciences, NIH, Durham, NC, 27709, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Armstrong
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006728:Hormones / Q000008:administration & dosage; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013004:Somatostatin / Q000008:administration & dosage; D046509:Tissue Culture Techniques
chemical_list: D006728:Hormones; D015221:Potassium Channels; D017481:Receptors, Somatostatin; D013004:Somatostatin; D000242:Cyclic AMP; D010749:Phosphoprotein Phosphatases; D000262:Adenylyl Cyclases
keywords: Hippocampus; K(+) channels; Neuronal excitability; Protein phosphatases; Somatostatin