Cell signaling underlying epileptic behavior

Abstract

Epilepsy is a complex disease, characterized by the repeated occurrence of bursts of electrical activity (seizures) in specific brain areas. The behavioral outcome of seizure events strongly depends on the brain regions that are affected by overactivity. Here we review the intracellular signaling pathways involved in the generation of seizures in epileptogenic areas. Pathways activated by modulatory neurotransmitters (dopamine, norepinephrine, and serotonin), involving the activation of extracellular-regulated kinases and the induction of immediate early genes (IEGs) will be first discussed in relation to the occurrence of acute seizure events. Activation of IEGs has been proposed to lead to long-term molecular and behavioral responses induced by acute seizures. We also review deleterious consequences of seizure activity, focusing on the contribution of apoptosis-associated signaling pathways to the progression of the disease. A deep understanding of signaling pathways involved in both acute- and long-term responses to seizures continues to be crucial to unravel the origins of epileptic behaviors and ultimately identify novel therapeutic targets for the cure of epilepsy.

Keywords: ERK; Fos; activity-dependent transcription; apoptosis; hippocampus; seizure.

Figure 1

Signaling pathways acutely activated in hippocampal neurons following seizures. Pathways downstream of glutamate, serotonin and dopamine receptors are illustrated. Seizures induce massive influx of Ca²⁺ through NMDA receptors and voltage-gated Ca²⁺ channels (in green), leading to CREB phosphorylation via ERK and calmodulin-dependent signaling, respectively (West et al., 2002). Serotonin and dopamine signaling modulate seizure-induced CREB phosphorylation via the activation of DARPP-32 and ERK1/2. Once phosphorylated, CREB promotes the transcription of activity-dependent genes such as BDNF and the IEGs fos and jun. The sustained induction of jun has been shown to switch on apoptotic cascades, whereas the pro-apoptotic role of fos induction has been questioned. Dendritic localization of BDNF mRNA and protein may also contribute to long-term excitability. The proposed scheme is a general (though not complete) summary of the intracellular pathways induced by seizures in the hippocampus. All the reported serotonin and dopamine receptor subtypes are expressed in the hippocampus, together with their signaling proteins (Meador-Woodruff et al., ; Perez and Lewis, ; Hannon and Hoyer, 2008). However, important differences may occur in different types of hippocampal neurons (e.g., dentate granule cells, pyramidal neurons), due to the different expression levels of these proteins. Abbreviations: AC, adenylate cyclase; CaM, calmodulin; CK1, casein kinase 1; DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32 kDa; D1R and D2R, dopamine receptors (D1 and D2 subtypes); ERK, extracellular-regulated kinase; GSK-3β, glycogen synthase kinase 3β; IEGs, immediate early genes; JNK, Jun-terminal kinase; NMDA, NMDA glutamate receptors; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PP-1, protein phosphatase 1; 5-HT, serotonin receptors. Question marks indicate that some pathways have been proposed but not clearly demonstrated.

Figure 2

Apoptosis-associated signaling pathways activated in neurons by seizures. Signaling pathways downstream of glutamate and Fas (death) receptors turn on BH3-only proteins of the Bcl-2 family, culminating in mitochondrial dysfunction and caspase-dependent and -independent cell death. The list is not complete and represents only some of the major pathways. Abbreviations: AIF, apoptosis-inducing factor; casp8, caspase-8; ER, endoplasmic reticulum; Fadd, Fas-associated death domain protein; FasR, Fas death receptor; JNK, Jun-terminal kinase; KA and NMDA, glutamate receptor subtypes; ROS, reactive oxygen species.