title: Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA. hal.blumenfeld@yale.edu
authors.forename: Hal
authors.initials: H
authors.lastname: Blumenfeld
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Klein
authors.forename: John
authors.initials: J
authors.lastname: Mission
authors.forename: Michael C
authors.initials: MC
authors.lastname: Chen
authors.forename: Maritza
authors.initials: M
authors.lastname: Rivera
authors.forename: Sulayman
authors.initials: S
authors.lastname: Dib-Hajj
authors.forename: Avis R
authors.initials: AR
authors.lastname: Brennan
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Hains
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D018450:Disease Progression; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007696:Kindling, Neurologic / Q000235:genetics*; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C100681:SCN8A protein, human; D015222:Sodium Channels