Abstracts

Hippocampal sclerosis (HS) is amongst the most common causes of medically refractory epilepsy in adults. Histologically HS is characterised by segmental neuronal loss, but the molecular mechanisms underlying this cell loss remain uncertain. Deregulation of the serine-threonine kinase cyclin dependent kinase 5 (cdk5) by p25, the calpain-mediated cleavage product of the physiological cdk5 activator p35, occurs in several cell death paradigms. Recently we demonstrated subfield-specific deregulation of cdk5 in human HS while animal models have shown that abnormal phosphorylation of the NMDA receptor might contribute to epileptogenesis. Intriguingly, when cdk5 is deregulated it phosphorylates NMDA receptors resulting in excitotoxicity. We therefore hypothesised that there might be abnormal cdk5-mediated phosphorylation of the NMDA receptor in HS., Surgically-resected cases of HS with adjacent histologically-normal temporal lobe and hippocampi from rats sacrificed at intervals following pilocarpine-induced status epilepticus were examined for cdk5, p25/p35, NeuN, NMDA and cdk5 phosphorylated NMDA receptor using immunohistochemistry, confocal microscopy, western blots and kinase assays., Animal models demonstrated a time-dependent increase in the ratio of p25:p35 and in p25-cdk5 activity following administration of pilocarpine. p25-cdk5 phosphorylated NMDA was not detected in control animals, but was strongly detected seven days after pilocarpine-induced status epilepticus and persisted until at least five months after pilocarpine treatment. Furthermore, despite neuronal loss, hippocampi from patients with HS had increased levels of p25-cdk5 phosphorylated NMDA compared to adjacent histologically-normal temporal lobe., Our results suggest that cdk5 might contribute to the neuronal loss, and potentially the epileptogenicity, of HS through direct phosphorylation of the NMDA receptor., (Supported by Medical Research Council, UK, Guarantors of [italic]Brain[/italic] and The Wellcome Trust.)