Abstracts

Hippocampal sclerosis is often seen in patients with medial temporal lobe epilepsy and the sclerotic hippocampus appears to be the origin of seizures in these patients. However little is known about the molecular nature of sclerosis. An increased T2 weighted signal in MRI and a higher apparent diffusion coefficient in diffusion weighted imaging are features of the sclerotic hippocampus, which indicate increased water content. Perturbed water homeostasis in the sclerotic hippocampus may be important in epileptogenesis as water transport appears to be coupled to K+ clearance and neuronal excitability. Aquaporin-4 (AQP4) is the predominant water channel in the brain. Expression of AQP4 was studied with quantitative real time PCR, light microscpic immunohistochemistry and high resolution immunogold labeling. Microarray analysis with Affymetrix GeneChip U133A was used to study gene expression patterns associated with AQP4. A significant increase in AQP4 was observed in the sclerotic but not in the non sclerotic hippocampus. This increase was positively correlated with the astrocytic marker glial fibrillary acidic protein (GFAP). Quantitative immunogold experiments showed that non-sclerotic hippocampi had a polarized distribution of AQP4 with the highest concentrations on the astrocytic end feet membranes facing blood vessels. In astrocytes of the sclerotic hippocampi this polarity was lost. High throughput gene expression analysis revealed that the increase in AQP4 was associated with a decreased expression of the dystrophin gene, whose protein is implicated in the anchoring of AQP4 to the perivascular end feet. We conclude that the perturbed expression of AQP4 and the loss of dystrophin may be critical factors underlying the loss of ion and water homeostasis in the hippocampus, and hypothesize that these changes may contribute to the epileptogenic properties of the sclerotic tissue. (Supported by NS048434 to NCdeL)