The role of glial membrane ion channels in seizures and epileptogenesis

Epilepsy is one of the most common neurological disorders, but the cellular basis of human epilepsy remains largely a mystery, and about 30% of all epilepsies remain uncontrolled. The vast bulk of epilepsy research has focused on neuronal and synaptic mechanisms, but the hypersynchronous firing that is the hallmark of epilepsy could also result from the abnormal function of glial cells by virtue of their critical role in the homeostasis of the brain's extracellular milieu. Therefore, increasing our understanding of glial pro-epileptic and epileptogenic mechanisms holds promise for the development of improved pharmacological treatments for epilepsy. Reactive astrocytes, a prominent feature of the human epileptic brain, undergo changes in their membrane properties and electrophysiology, in particular in the expression of membrane K+ and Na+ channels, which result in pro-epileptic changes in their homeostatic control of the extracellular space. Nonetheless, a causal role for reactive astrocytosis in epilepsy has been difficult to determine because glial reactivity can be induced by a wide range of central nervous system insults, including epileptic seizures themselves. A complicating factor is that different insults to the central nervous system result in reactive astrocytes with different membrane properties. Therefore, most animal models of epilepsy preselect the properties of the reactive glia studied. Finally, a causal role for reactive glia in epilepsy cannot be firmly established by examining human epileptic tissue because of its chronic and pharmacoresistant pathological condition that warranted the surgical intervention. Therefore, the development of clinically relevant models of reactive astrocytosis, and of symptomatic epileptogenesis, is needed to investigate the issue. A recently developed model of post-traumatic epileptogenesis in the rat, where chronic spontaneous recurrent seizures develop after a single event of a clinically relevant form of closed head injury, the fluid percussion injury, offers hope to help understand the role of reactive glia in seizures and epileptogenesis and lead to the development of improved therapies. (C) 2004 Elsevier Inc. All rights reserved.