Recent studies have implicated glial cells in novel physiological roles in the CNS, such as
modulation of synaptic transmission, so it is possible that glial cells might have a functional
role in the hyperexcitability that is characteristic of epilepsy. Indeed, alterations in
distinct astrocyte membrane channels, receptors and transporters have all been associated with
the epileptic state. This paper focuses on the potential roles of the glial water channel
aquaporin-4 (AQP4) in modulating brain excitability and in epilepsy. We review studies of
seizure phenotypes, K+ homeostasis and extracellular space physiology of mice that
lack AQP4 (AQP4−/− mice) and discuss the human studies
demonstrating alterations of AQP4 in specimens of human epilepsy tissue. We conclude with new
studies of AQP4 regulation by seizures and discuss its potential role in the development of
epilepsy (epileptogenesis). Although many questions remain unanswered, the available data
indicate that AQP4 and its molecular partners might represent important new therapeutic
targets.