Aquaporin‐4 and epilepsy

Abstract

Recent studies have implicated glial cells in modulation of synaptic transmission, so it is plausible that glial cells may have a functional role in the hyperexcitability characteristic of epilepsy. Indeed, alterations in distinct astrocyte membrane channels, receptors, and transporters have all been associated with the epileptic state. This review focuses on the potential roles of the glial water channel aquaporin-4 (AQP4) in modulation of brain excitability and in epilepsy. We will review studies of mice lacking AQP4 (Aqp4 2/2 mice) or a-syntrophin (an AQP4 anchoring protein) and discuss the available human studies demonstrating alterations of AQP4 in human epilepsy tissue specimens. We will conclude with new studies of AQP4 regulation and discuss the potential role of AQP4 in the development of epilepsy (epileptogenesis). While many questions remain unanswered, the available data indicate that AQP4 and its molecular partners may represent important new therapeutic targets. V

Different Aquaporin-4 Expression in Glioblastoma Multiforme Patients with and without Seizures

“…In animal models, the relationship between AQP-4 expression and epileptic seizures is complex, even if the results are rather homogeneous. AQP-4 knockout mice had increased resistance to development of induced seizures (20). However, when induced seizures occur, their severity is greater than in wild-type mice (20).…”

“…AQP-4 is the main component of the so-called ortogonal array of particles (OAPs), which are preferentially located at the tip of astrocytic end feet. Furthermore, in the context of OAPs, AQP-4 forms part of a macromolecular complex, including dystrophyn, dystroglycan and voltage-gated potassium channel type 4.1 (18)(19)(20). Functional coupling of AQP-4 was also suggested with chloride channels and the electroneural cotransporter potassium-chloride cotransporter-1 (KCC-1) (19).…”

“…Control of cell volume is linked to the regulation of (a) extracellular space volume, (b) extracellular potassium concentration and (c) efflux of glutamate and other osmolytes such as taurine (19). It was demonstrated that as a consequence of cells swelling (for instance after high frequency neuronal firing or during systemic hyponatriemia), there is a compensatory efflux of potassium, chloride and glutamate from the cells (19,20). The net effect of increased extracellular potassium and glutamate concentration is a depolarization of neuronal membrane, with increased excitability (19,20).…”

“…It was demonstrated that as a consequence of cells swelling (for instance after high frequency neuronal firing or during systemic hyponatriemia), there is a compensatory efflux of potassium, chloride and glutamate from the cells (19,20). The net effect of increased extracellular potassium and glutamate concentration is a depolarization of neuronal membrane, with increased excitability (19,20). Stimulation of astrocytes as well as modulation of asrocytic volume and chloride currents are important in determining synchronization of neuronal firing (19,20).…”

“…The net effect of increased extracellular potassium and glutamate concentration is a depolarization of neuronal membrane, with increased excitability (19,20). Stimulation of astrocytes as well as modulation of asrocytic volume and chloride currents are important in determining synchronization of neuronal firing (19,20). Increased excitability along with hypersynchrony are critical factors in the development of epileptic seizures (15,21).…”