Dysregulation of sodium channel expression in cortical neurons in a rodent model of absence epilepsy.
Due to the involvement of cortical neurons in spike-wave discharge (SWD) initiation, and the contribution of voltage-gated sodium channels (VGSCs) to neuronal firing, we examined alterations in the expression of VGSC mRNA and protein in cortical neurons in the WAG/Rij absence epileptic rat. WAG/Rij rats were compared to age-matched Wistar control rats at 2, 4, and 6 months. Continuous EEG data was recorded, and percent time in SWD was determined. Tissue from different cortical locations from WAG/Rij and Wistar rats was analyzed for VGSC mRNA (by quantitative PCR) and protein (by immunocytochemistry). SWDs increased with age in WAG/Rij rats. mRNA levels for sodium channels Nav1.1 and Nav1.6, but not Nav1.2, were found to be up-regulated selectively within the facial somatosensory cortex (at AP +0.0, ML +6.0 mm). Protein levels for Nav1.1 and Nav1.6 were up-regulated in layer II-IV cortical neurons in this region of cortex. No significant changes were seen in adjacent regions or other brain areas, including the pre-frontal and occipital cortex. In the WAG/Rij model of absence epilepsy, we identified a specific region of cortex, in layer II-IV neurons on the lateral convexity of the cortex in the facial somatosensory area, where mRNA and protein expression of sodium channel genes Nav1.1 and Nav1.6 are up-regulated. This region of cortex approximately matches the electrophysiologically determined region of seizure onset. Changes in the expression of Nav1.1 and Nav1.6 parallel age-dependent increases in seizure frequency and duration.
Klein
Joshua P
JP
Department of Neurology, Yale University School of Medicine, New Haven, and Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.
Khera
Davender S
DS
Nersesyan
Hrachya
H
Kimchi
Eyal Y
EY
Waxman
Stephen G
SG
Blumenfeld
Hal
H
D000200:Action Potentials / Q000502:physiology; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology*
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D015222:Sodium Channels