Molecular Signaling Mechanisms Underlying Epileptogenesis

Epilepsy, a disorder of recurrent seizures, is a common and frequently devastating neurological condition. Available therapy is only symptomatic and often ineffective. Understanding epileptogenesis, the process by which a normal brain becomes epileptic, may help identify molecular targets for drugs that could prevent epilepsy. A number of acquired and genetic causes of this disorder have been identified, and various in vivo and in vitro models of epileptogenesis have been established. Here, we review current insights into the molecular signaling mechanisms underlying epileptogenesis, focusing on limbic epileptogenesis. Study of different models reveals that activation of various receptors on the surface of neurons can promote epileptogenesis; these receptors include ionotropic and metabotropic glutamate receptors as well as the TrkB neurotrophin receptor. These receptors are all found in the membrane of a discrete signaling domain within a particular type of cortical neuron—the dendritic spine of principal neurons. Activation of any of these receptors results in an increase Ca2+concentration within the spine. Various Ca2+-regulated enzymes found in spines have been implicated in epileptogenesis; these include the nonreceptor protein tyrosine kinases Src and Fyn and a serine-threonine kinase [Ca2+-calmodulin–dependent protein kinase II (CaMKII)] and phosphatase (calcineurin). Cross-talk between astrocytes and neurons promotes increased dendritic Ca2+ and synchronous firing of neurons, a hallmark of epileptiform activity. The hypothesis is proposed that limbic epilepsy is a maladaptive consequence of homeostatic responses to increases of Ca2+concentration within dendritic spines induced by abnormal neuronal activity. The epilepsies, disorders of recurrent seizures, affect about 1% of the population worldwide. Available therapy is symptomatic in that drugs inhibit seizures but are not disease-modifying; that is, no effective pharmacological prevention or cure has been identified. The term "epileptogenesis" refers to the process by which a normal brain becomes epileptic. Understanding the cellular mechanisms of epileptogenesis in molecular terms may help identify molecular targets for which small-molecule therapeutics can be developed to prevent epileptogenesis in individuals at high risk. A number of acquired and genetic causes of this disorder have been identified, and various in vivo and in vitro models of epileptogenesis have been established. The objective of this STKE Review, with 5 figures, 2 tables, and 199 references, is to review current insights into the molecular signaling mechanisms underlying epileptogenesis, focusing on limbic epileptogenesis in particular.