ReviewTurning down the volume: Astrocyte volume change in the generation and termination of epileptic seizures

- Reductions in CNS extracellular space precede and promote seizure activity.
- Astrocytes regulate neuronal excitability through water, K+, and glutamate uptake.
- Water and K+ uptake can swell astrocytes and shrink extracellular space.
- Swollen astrocytes may release glutamate through volume-regulated channels.
- Astrocyte swelling may promote neuronal hyperexcitability leading to seizure.

Approximately 1% of the global population suffers from epilepsy, a class of disorders characterized by recurrent and unpredictable seizures. Of these cases roughly one-third are refractory to current antiepileptic drugs, which typically target neuronal excitability directly. The events leading to seizure generation and epileptogenesis remain largely unknown, hindering development of new treatments. Some recent experimental models of epilepsy have provided compelling evidence that glial cells, especially astrocytes, could be central to seizure development. One of the proposed mechanisms for astrocyte involvement in seizures is astrocyte swelling, which may promote pathological neuronal firing and synchrony through reduction of the extracellular space and elevated glutamate concentrations. In this review, we discuss the common conditions under which astrocytes swell, the resultant effects on neural excitability, and how seizure development may ultimately be influenced by these effects.