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.

Progressive Seizure Aggravation in the Repeated 6-Hz Corneal Stimulation Model Is Accompanied by Marked Increase in Hippocampal p-ERK1/2 Immunoreactivity in Neurons

“…These markers have been found to be widely expressed in the hippocampus of animals exposed to seizures induced by kainate (Kim et al, 1994; Crespo-Biel et al, 2007), pilocarpine (Garrido et al, 1998; Berkeley et al, 2002; Houser et al, 2008), bicuculline (Gass et al, 1993; Ben et al, 2014), and dopamine D 1 receptor agonists (Bozzi et al, 2011; Gangarossa et al, 2011, 2014; Bozzi and Borrelli, 2013). We also found p-ERK1/2 to be induced by audiogenic seizures in mice affected by fragile X syndrome (Curia et al, 2013) and, interestingly, changes in p-ERK1/2 have been associated to a different sensitivity to proconvulsant stimuli (Glazova et al, 2015).…”

Confirmation that the AKT1 (rs2494732) Genotype Influences the Risk of Psychosis in Cannabis Users

“…The AKT1 gene is an attractive candidate because it codes for a protein kinase that forms an integral part of the dopamine receptor signaling cascade in the striatum (9). Moreover, in vivo administration to mice of delta-9-tetrahydrocannabinol (delta-9-TCH), the active ingredient in cannabis, activates this signaling cascade via AKT1 phosphorylation (10,11).…”

Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition

“…The prototypical and most characterized immediate early gene-encoded transcription factor is c-Fos which is expressed with a peak of 30 to 90 minutes after stimulation (Herrera and Robertson, 1996). There is ample literature describing neuronal c-Fos induction following kindling and other seizure models (Barone et al, 1993; Bozzi et al, 2011; Chiasson et al, 1995; Dragunow and Faull, 1989; Dragunow and Robertson, 1988; Morgan and Curran, 1991a, b; Motte et al, 1997). Furthermore, several studies have demonstrated a correlation between the expansion of c-Fos induction from limbic areas to the cerebral cortex and the progression of epileptic seizures (Andre et al, 1998; Clark et al, 1991; Ebert and Loscher, 1995; Hiscock et al, 2001; Simler et al, 1999; Szyndler et al, 2009; Willoughby et al, 1997).…”