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 neur...

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Published in:	Neuroscience Vol. 167; no. 1; pp. 154 - 162
Main Authors:	Cortez, M.A, Li, C, Whitehead, S.N, Dhani, S.U, D'Antonio, C, Huan, L.J, Bennett, S.A.L, Snead, O.C, Bear, C.E
Format:	Journal Article
Language:	English
Published:	United States Elsevier Ltd 28-04-2010
Subjects:	Aging Animals astrocyte activation Astrocytes - physiology Bicuculline - pharmacology CA3 Region, Hippocampal - drug effects CA3 Region, Hippocampal - pathology CA3 Region, Hippocampal - physiopathology Cell Death - physiology chloride channel Chloride Channels - deficiency Chloride Channels - genetics Chloride Channels - metabolism electrocorticographic Electroencephalography GABA Antagonists - pharmacology hippocampus Hippocampus - drug effects Hippocampus - pathology Hippocampus - physiopathology Immunoblotting inflammation interictal spikes Mice Mice, Knockout Nerve Degeneration - pathology Nerve Degeneration - physiopathology Neurology Neurons - drug effects Neurons - pathology Neurons - physiology Picrotoxin - pharmacology electrocorticogram Hi hippocampus interictal spikes TdT H&E MGPY Methyl Green Pyronine Y Hematoxylin and Eosin astrocyte activation GFAP TdT-mediated dUTP nick end labeling TUNEL chloride channel inflammation ECoG terminal deoxynucleotidyl transferase glial fibrillary acidic protein electrocorticographic
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2010.01.042