title: Disruption of ClC-2 expression is associated with progressive neurodegeneration in aging mice.
abstract: 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.
authors.affiliation: Programmes in Brain and Behaviour Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Cortez
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: S N
authors.initials: SN
authors.lastname: Whitehead
authors.forename: S U
authors.initials: SU
authors.lastname: Dhani
authors.forename: C
authors.initials: C
authors.lastname: D'Antonio
authors.forename: L J
authors.initials: LJ
authors.lastname: Huan
authors.forename: S A L
authors.initials: SA
authors.lastname: Bennett
authors.forename: O C
authors.initials: OC
authors.lastname: Snead
authors.forename: C E
authors.initials: CE
authors.lastname: Bear
mesh_terms: D000375:Aging; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001640:Bicuculline / Q000494:pharmacology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000090007:CLC-2 Chloride Channels; D016923:Cell Death / Q000502:physiology; D018118:Chloride Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004569:Electroencephalography; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010852:Picrotoxin / Q000494:pharmacology
chemical_list: D001640:Bicuculline; D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; D018756:GABA Antagonists; D010852:Picrotoxin