Abstracts

Spike-wave discharges (SWDs) associated with absence seizures are thought to arise from rhythmic oscillatory burst firing of cortical and thalamic neurons. Neuronal voltage-gated sodium channels produce transient and persistent currents which can initiate these discharges. WAG/Rij rats exhibit spontaneous electrographic seizures characterized by bilaterally synchronous and symmetric SWDs, which occur at 7-11 Hz and are typically 2-8 s in duration. The anatomical region of seizure onset in WAG/Rij rats has been localized to the facial region of the somatosensory cortex. In this study, we asked whether there are differences in sodium channel expression in the cortex of WAG/Rij rats compared to control (non-epileptic) rats. We localized altered sodium channel expression to a specific region of cortex, and furthermore to a specific population of neurons within the cortical mantle. This data was correlated to EEG recordings to establish an age-dependent link between SWD frequency and duration, and extent of sodium channel dysregulation.
WAG/Rij rats were compared to age-matched Wistar control rats at 2, 4, and 6 months. Continuous EEG data was recorded from fixed electrodes at AP+2.0, ML+2.0, and AP-6.0, ML+2.0 mm, and percent time in SWD firing pattern was calculated for all animals. Tissue plugs from different cortical locations were dissected for analysis of sodium channel mRNA levels in epileptic rats compared to control rats. Sodium channel protein levels in cortical neurons were determined 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 up-regulated in the facial somatosensory cortex (at AP+0.0, ML+6.0). Protein levels for Nav1.1 and Nav1.6 were up-regulated in layer II-IV cortical neurons in this region of cortex. Phospho-CREB expression was also up-regulated in these neurons. No significant changes were seen in other cortical regions. Expression of Nav1.1 and Nav1.6 parallels the age-dependent increase in SWD seizures in WAG/Rij rats.
Expression of sodium channels Nav1.1 and Nav1.6, but not Nav1.2, is up-regulated in layer II-IV cortical neurons of the facial somatosensory cortex in absence epileptic WAG/Rij rats compared to control Wistar rats, as detected by quantitative PCR and immunocytochemistry. The age-dependent up-regulation of Nav1.1 and Nav1.6 parallels the age-dependent increase in seizure frequency. Currents generated by Nav1.1 and Nav1.6 may lead to neuronal hyperexcitability and burst firing.
[Supported by: The Medical Research Service and Rehabilitation Research Service, Department of Veterans Affairs, and by grants from the Paralyzed Veterans of America and the Eastern Paralyzed Veterans Association (to S.G.W.); and by NIH NS02060 and the Patterson Trust (to H.B.). J.P.K. is supported by the NIH Medical Scientist Training Program. ]