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

J Neurochem. 2007 Aug;102(4):1009-23. doi: 10.1111/j.1471-4159.2007.04579.x. Epub 2007 Apr 17.

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 Ca(2+) imaging revealed a bidirectional modulation of N-methyl-D-aspartate (NMDA) -mediated Ca(2+) responses and reduced KCl-mediated Ca(2+) responses in neonatal cultured hippocampal neurons after phosphatase inhibition. While OA inhibited NMDA-induced Ca(2+) 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 Ca(2+) responses at higher concentrations (100 nmol/L). Changes in Ca(2+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cantharidin / pharmacology
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists / pharmacology
  • Female
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • In Vitro Techniques
  • N-Methylaspartate / pharmacology
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Okadaic Acid / pharmacology
  • Patch-Clamp Techniques / methods
  • Phosphoprotein Phosphatases / metabolism*
  • Potassium Chloride / pharmacology
  • Rats
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Time Factors
  • tau Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • tau Proteins
  • Okadaic Acid
  • N-Methylaspartate
  • Potassium Chloride
  • Phosphoprotein Phosphatases
  • Cantharidin
  • Calcium