Structural consequences of Kcna1 gene deletion and transfer in the mouse hippocampus

Purpose: Mice lacking the KvI.I potassium channel a subunit encoded by the KcnaI gene develop recurrent behavioral seizures early in life. We examined the neuropathological consequences of seizure activity in the KvI.I-/- (knock-out) mouse, and explored the effects of injecting a viral vector carrying the deleted KcnaI gene into hippocampal neurons. Methods: Morphological techniques were used to assess neuropathological patterns in hippocampus of KvI.I-/- animals. Immunohistochemical and biochemical techniques were used to monitor ion channel expression in KvI.I-/- brain. Both wildtype and knockout mice were injected (bilaterally into hippocampus) with an HSVI amplicon vector that contained the rat KcnaI subunit gene and/or the E. coli lacZ reporter gene. Vector-injected mice were examined to determine the extent of neuronal infection. Results: Video/EEG monitoring confirmed interictal abnormalities and seizure occurrence in KvI.I-/- mice. Neuropathological assessment suggested that hippocampal damage ( silver stain) and reorganization (Timm stain) occurred only after animals had exhibited severe prolonged seizures ( status epilepticus). Ablation of KcnaI did not result in compensatory changes in expression levels of other related ion channel subunits. Vector injection resulted in infection primarily of granule cells in hippocampus, but the number of infected neurons was quite variable across subjects. KcnaI immunocytochemistry showed "ectopic" Kv1.1 a channel subunit expression. Conclusions: KcnaI deletion in mice results in a seizure disorder that resembles-electrographically and neuropathologically-the patterns seen in rodent models of temporal lobe epilepsy. HSVI vector-mediated gene transfer into hippocampus yielded variable neuronal infection. .