Modulation of hippocampal calcium signalling and plasticity by serine/threonine protein phosphatases

David J. Koss, Kathleen P. Hindley, Gernot Riedel, Bettina Platt

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Kinases and phosphatases act antagonistically to maintain physiological phosphorylation/dephosphorylation at numerous intracellular sites critical for neuronal signalling. In this study, it was found that inhibition of serine/threonine phosphatases by exposure of hippocampal slices to okadaic acid (OA) or cantharidin (CA; 100 nmol/L) for 2 h resulted in reduced basal synaptic transmission and blocked the induction of synaptic plasticity in the form of long-term potentiation as determined by electrophysiological analysis. Fura-2 Ca2+ imaging revealed a bidirectional modulation of N-methyl-d-aspartate (NMDA) -mediated Ca2+ responses and reduced KCl-mediated Ca2+ responses in neonatal cultured hippocampal neurons after phosphatase inhibition. While OA inhibited NMDA-induced Ca2+ influx both acutely and after incubation, CA-enhanced receptor-mediated Ca 2+ signalling at low concentrations (1 nmol/L) but reduced NMDA and KCl-mediated Ca2+ responses at higher concentrations (100 nmol/L). Changes in Ca2+ signalling were accompanied by increased phosphorylation of cytoskeletal proteins tau and neurofilament and the NMDA receptor subunit NR1 in selective treatments. Incubation with OA (100 nmol/L) also led to the disruption of the microtubule network. This study highlights novel signalling effects of prolonged inhibition of protein phosphatases and suggests reduced post-synaptic signalling as a major mechanism for basal synaptic transmission and long-term potentiation impairments.

Original languageEnglish
Pages (from-to)1009-1023
Number of pages15
JournalJournal of Neurochemistry
Volume102
Issue number4
Early online date16 Mar 2007
DOIs
Publication statusPublished - Aug 2007

Keywords

  • Alzheimer's disease
  • Long-term potentiation
  • N-methyl-d-aspartate
  • Okadaic acid
  • Phosphorylation
  • Synaptic transmission
  • Tau

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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