Molecular Signaling Mechanisms Underlying Epileptogenesis

Abstract

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.

Mutation I810N in the α3 isoform of Na + ,K + -ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

“…5). Chronic over-stimulation of NMDA receptors is known to induce seizures (18,19). Hence, synergism between ␣3 Na ϩ ,K ϩ -ATPase and NMDA receptor activities may contribute to determine the epileptic propensity, possibly through disruption of calcium metabolism.…”

“…S5). Over-stimulation of NMDA receptors induces seizures (18,19), and the observed posttetanic increase in E-S coupling in CA1 pyramidal neurons may result from an NMDA receptor-dependent long-term depression (LTD) of feed-forward GABA A -mediated inhibition (19).…”

Neurotrofinas na epilepsia do lobo temporal

“…Nestes modelos ocorre um estado de atividade epiléptica contínua denominado Status Epilepticus (SE), seguido por um período latente livre de crises epilépticas. Após este período, iniciam-se crises espontâneas recorrentes 21 .…”

Genes e epilepsia I: epilepsia e alterações genéticas

“…Neste caso, diz-se que a epilepsia é própria do indivíduo (idios -próprio; pathos -doença). Hoje, sabese que a maioria das epilepsias idiopáticas é causada por mutações genéticas 6,13 .…”

“…Uma das frentes de estudo que tem evoluído muito nas últimas décadas diz respeito às investigações de vias moleculares associadas ao processo epileptogênico. Muitos esforços têm sido realizados para identificar genes associados à epilepsia 6,7 . Neste trabalho, descrevemos e discutimos os resultados mais relevantes, obtidos em estudos com pacientes e em modelos experimentais.…”