Store-operated Calcium Entry Modulates Neuronal Network Activity in a Model of Chronic Epilepsy

Exp Neurol. 2011 Dec;232(2):185-94. doi: 10.1016/j.expneurol.2011.08.022. Epub 2011 Aug 30.

Abstract

Store-operated Ca(2+) entry (SOCE) over the plasma membrane is activated by depletion of intracellular Ca(2+) stores and has only recently been shown to play a role in CNS processes like synaptic plasticity. However, the direct effect of SOCE on the excitability of neuronal networks in vitro and in vivo has never been determined. We confirmed the presence of SOCE and the expression of the calcium sensors STIM1 and STIM2, which convey information about the calcium load of the stores to channel proteins at the plasma membrane, in neurons and astrocytes. Inhibition of SOCE by pharmacological agents 2-APB and ML-9 reduced the steady-state neuronal Ca(2+) concentration, reduced network activity, and increased synchrony of primary neuronal cultures grown on multi-electrode arrays, which prompted us to elucidate the relative expression of STIM proteins in conditions of pathologic excitability. Both proteins were increased in brains of chronic epileptic rodents and strongly expressed in hippocampal specimens from medial temporal lobe epilepsy patients. Pharmacologic inhibition of SOCE in chronic epileptic hippocampal slices suppressed interictal spikes and rhythmized epileptic burst activity. Our results indicate that SOCE modulates the activity of neuronal networks in vitro and in vivo and delineates SOCE as a potential drug target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Calcium / metabolism*
  • Calcium-Binding Proteins / metabolism*
  • Cell Adhesion Molecules / metabolism
  • Cell Membrane / metabolism
  • Chronic Disease
  • Entorhinal Cortex / cytology
  • Entorhinal Cortex / physiopathology
  • Epilepsy, Temporal Lobe / metabolism*
  • Epilepsy, Temporal Lobe / physiopathology
  • Hippocampus / cytology
  • Hippocampus / physiopathology
  • Humans
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism*
  • Neoplasm Proteins / metabolism
  • Nerve Net / metabolism
  • Nerve Net / physiopathology
  • Neurons / cytology
  • Neurons / metabolism*
  • Organ Culture Techniques
  • Primary Cell Culture
  • Rats
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2

Substances

  • Calcium-Binding Proteins
  • Cell Adhesion Molecules
  • Membrane Glycoproteins
  • Membrane Proteins
  • Neoplasm Proteins
  • STIM1 protein, human
  • STIM2 protein, human
  • STIM2 protein, rat
  • Stim1 protein, rat
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2
  • Calcium