Disruption of ClC-2 expression is associated with progressive neurodegeneration in aging mice

Neuroscience. 2010 Apr 28;167(1):154-62. doi: 10.1016/j.neuroscience.2010.01.042. Epub 2010 Jan 29.


Heterozygous mutations in ClC-2 have been associated in rare cases with increased susceptibility to generalized, idiopathic epilepsy. Initially, it was hypothesized that mutations in ClC-2 may be associated with epilepsy due to a direct role for ClC-2 in the modification of hippocampal neuronal excitability. However, the absence of an overt seizure-susceptibility phenotype in young ClC-2 knockout (KO) mice rendered this hypothesis- implausible. A recent study of older ClC-2 KO mice (>6 months) revealed abnormalities in the myelin of central axons and a subtle defect in the neuronal function in the central auditory pathway. These findings prompted us to re-examine hippocampal neuron morphology and excitability in older ClC-2 KO mice. Interestingly, electrocorticographic recordings obtained in older mice revealed spontaneous interictal spikes which are a marker of perturbed hippocampal neurotransmission with a resultant increase in excitation. This electrophysiological defect was associated with astrocyte activation and evidence of neuronal degeneration in the CA3 region of the hippocampus of these older mice. Together, these findings raise the possibility that ClC-2 expression plays a subtle neuroprotective role in the aging hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Astrocytes / physiology
  • Bicuculline / pharmacology
  • CA3 Region, Hippocampal / drug effects
  • CA3 Region, Hippocampal / pathology
  • CA3 Region, Hippocampal / physiopathology
  • CLC-2 Chloride Channels
  • Cell Death / physiology
  • Chloride Channels / deficiency
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Electroencephalography
  • GABA Antagonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Hippocampus / physiopathology*
  • Immunoblotting
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology*
  • Neurons / drug effects
  • Neurons / pathology
  • Neurons / physiology*
  • Picrotoxin / pharmacology


  • CLC-2 Chloride Channels
  • Chloride Channels
  • GABA Antagonists
  • Picrotoxin
  • Bicuculline