Regulation of Brain Water: Is there a Role for Aquaporins in Epilepsy?

Abstract

Aquaporin-4 Is Increased in the Sclerotic Hippocampus in Human Temporal Lobe Epilepsy Lee TS, Eid T, Mane S, Kim JH, Spencer DD, Ottersen OP, de Lanerolle NC Acta Neuropathol (Berl) 2004;108:493–502 The hippocampus of patients with mesial temporal lobe epilepsy is often hardened and shrunken, a condition known as sclerosis. MRI reveals an increase in the T2-weighted signal, whereas diffusion-weighted imaging shows a higher apparent diffusion coefficient in sclerotic hippocampi, indicating increased water content. As water transport appears to be coupled to K+ clearance and neuronal excitability, the molecular basis of the perturbed water homeostasis in the sclerotic hippocampus was explored. The expression of aquaporin-4 (AQP-4), the predominant water channel in the brain, was studied with quantitative real-time polymerase chain reaction analysis, light-microscopic immunohistochemistry, and high-resolution immunogold labeling. A significant increase in AQP-4 was observed in sclerotic, but not in nonsclerotic, hippocampi obtained from patients with medically intractable temporal lobe epilepsy. This increase was positively correlated with an increase in the astrocyte marker glial fibrillary acidic protein. AQP-4 was localized to the plasma membranes of astrocytes including the perivascular endfeet. Gene expression associated with increased AQP-4 was evaluated by high-throughput gene-expression analysis with Affymetrix GeneChip U133A, and related gene networks were investigated with Ingenuity Pathways Analysis. AQP-4 expression was associated with a decrease in expression of the dystrophin gene, a protein implicated in the anchoring of AQP-4 in perivascular endfeet. The decreased expression of dystrophin may indicate a loss of polarity in the distribution of AQP-4 in astrocytes. We conclude that the perturbed expression of AQP-4 and dystrophin may be one factor underlying the loss of ion and water homeostasis in the sclerotic hippocampus and hypothesize that the reported changes may contribute to the epileptogenic properties of the sclerotic tissue.