Changes in the mRNAs encoding voltage-gated sodium channel types II and III in human epileptic hippocampus

Studies with animal seizure models have indicated that changes in temporal and spatial expression of voltage-gated sodium channels may be important in the pathology of epilepsy. Here, by using in situ hybridisation with previ ously characterised subtype-selective oligonucleotide probes [Whitaker et a l. (2000) J. Comp. Neurol. 422, 123-139], we have compared the cellular exp ression of all four brain alpha -subunit sodium channel mRNAs in 'normal' a nd epileptic hippocampi from humans. Neuronal cell loss was observed in all regions of the hippocampus of diseased patients, indicating that sclerosis had occurred. Losses of up to 40% compared to post-mortem controls were ob served which were statistically significant in all regions studied (dentate gyrus, hilus, and CA1-3). To assess mRNA levels of the different a-subtypes in specific subregions, c ontrol and diseased tissue sections were hybridised to subtype-specific pro bes. To quantify any changes in expression while allowing for cell loss, th e sections were processed for liquid emulsion autoradiography and grain cou nts were performed on populations of individual neurones in different subre gions. No significant differences were found in the expression of type I an d VI mRNAs. In contrast, a significant down-regulation of type II mRNA was observed in the epileptic tissue in the remaining pyramidal cells of CA3 (7 1 +/- 7% of control, P < 0.01), CA2 (81 +/- 8% of control, P < 0.05) and CA 1 (72 +/- 6% of control, P < 0.05) compared with control tissue. Additional ly, a significant up-regulation in type III mRNA in epileptic CA4 pyramidal cells (145 +/- 7% of control, P < 0.05) was observed. It is not clear whether these changes play a causal role in human epilepsy or whether they are secondary to seizures or drug treatment; further studie s are necessary to investigate these alternatives. However, it is likely th at such changes would affect the intrinsic excitability of hippocampal neur ones. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved .