Surviving granule cells of the sclerotic human hippocampus have reduced Ca(2+) influx because of a loss of calbindin-D(28k) in temporal lobe epilepsy.
In mesial temporal lobe epilepsy (mTLE), the predominant form of epilepsy in adults, and in animal models of the disease, there is a conspicuous loss of the intracellular Ca(2+)-binding protein calbindin-D(28k) (CB) from granule cells (GCs) of the dentate gyrus. The role of this protein in nerve cell function is controversial, but here we provide evidence for its role in controlling Ca(2+) influx into human neurons. In patients with Ammon's horn sclerosis (AHS), the loss of CB from GCs markedly increased the Ca(2+)-dependent inactivation of voltage-dependent Ca(2+) currents (I(Ca)), thereby diminishing Ca(2+) influx during repetitive neuronal firing. Introducing purified CB into GCs restored Ca(2+) current inactivation to levels observed in cells with normal CB content harvested from mTLE patients without AHS. Our data are consistent with the possibility of neuroprotection secondary to the CB loss. By limiting Ca(2+) influx through an enhanced Ca(2+)-dependent inactivation of voltage-dependent Ca(2+) channels during prolonged neuronal discharges, the loss of CB may contribute to the resistance of surviving human granule cells in AHS.
Nägerl
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Department of Neurology, University of California at Los Angeles School of Medicine, Los Angeles, California 90095, USA.
Mody
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Jeub
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Lie
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Elger
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Beck
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D000200:Action Potentials / Q000502:physiology; D000328:Adult; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D018891:Dentate Gyrus / Q000473:pathology*; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D064030:S100 Calcium Binding Protein G / Q000032:analysis / Q000378:metabolism*; D012598:Sclerosis
D064026:Calbindins; D015220:Calcium Channels; D064030:S100 Calcium Binding Protein G; D002118:Calcium