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Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis
Author(s) -
Blumenfeld Hal,
Lampert Angelika,
Klein Joshua P.,
Mission John,
Chen Michael C.,
Rivera Maritza,
DibHajj Sulayman,
Brennan Avis R.,
Hains Bryan C.,
Waxman Stephen G.
Publication year - 2009
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2008.01710.x
Subject(s) - kindling , hippocampal formation , sodium channel , epileptogenesis , neuroscience , fascia dentata , kindling model , hippocampus , endocrinology , in situ hybridization , medicine , chemistry , epilepsy , biology , messenger rna , sodium , dentate gyrus , biochemistry , organic chemistry , gene
Summary Purpose: Central nervous system plasticity is essential for normal function, but can also reinforce abnormal network behavior, leading to epilepsy and other disorders. The role of altered ion channel expression in abnormal plasticity has not been thoroughly investigated. Nav1.6 is the most abundantly expressed sodium channel in the nervous system. Because of its distribution in the cell body and axon initial segment, Nav1.6 is crucial for action potential generation. The goal of the present study was to investigate the possible role of changes in Nav1.6 expression in abnormal, activity‐dependent plasticity of hippocampal circuits. Methods: We studied kindling, a form of abnormal activity‐dependent facilitation. We investigated: (1) sodium channel protein expression by immunocytochemistry and sodium channel messenger RNA (mRNA) by in situ hybridization, (2) sodium current by patch clamp recordings, and (3) rate of kindling by analysis of seizure behavior. The initiation, development, and expression of kindling in wild‐type mice were compared to Nav1.6 +/− med tg mice, which have reduced expression of Nav1.6. Results: We found that kindling was associated with increased expression of Nav1.6 protein and mRNA, which occurred selectively in hippocampal CA3 neurons. Hippocampal CA3 neurons also showed increased persistent sodium current in kindled animals compared to sham‐kindled controls. Conversely, Nav1.6 +/− med tg mice resisted the initiation and development of kindling. Discussion: These findings suggest an important mechanism for enhanced excitability, in which Nav1.6 may participate in a self‐reinforcing cycle of activity‐dependent facilitation in the hippocampus. This mechanism could contribute to both normal hippocampal function and to epilepsy and other common nervous system disorders.