Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis
Hal Blumenfeld
Departments of Neurology
Neurobiology
Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.
Search for more papers by this authorAngelika Lampert
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorJoshua P. Klein
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorSulayman Dib-Hajj
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorBryan C. Hains
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorStephen G. Waxman
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorHal Blumenfeld
Departments of Neurology
Neurobiology
Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, U.S.A.
Search for more papers by this authorAngelika Lampert
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorJoshua P. Klein
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorSulayman Dib-Hajj
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorBryan C. Hains
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorStephen G. Waxman
Departments of Neurology
Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA
Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut, U.S.A.
Search for more papers by this authorSummary
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 +/−medtg 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 +/−medtg 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.
Supporting Information
Supplementary Data 1: Rat immunocytochemistry results for Nav1.1, 1.2 and 1.6 (Table S1) and rat in situ hybridization results for Nav1.6 (Table S2).
Table S1: Rat immunocytochemistry results for Nav1.1, 1.2 and 1.6.
Table S2: Rat in situ hybridization results for Nav1.6.
Supplementary Data 2: Properties of voltage-gated sodium currents in dissociated adult CA3 neurons of kindled and sham treated WT mice, and Nav1.6 +/- med mice.
Supplementary Data 3: In Nav1.6 +/- mice, kindling tends to increase persistent sodium current in CA3 neurons.
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