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Prolonged seizures (status epilepticus) are associated with brain region-specific regulation of apoptosis-associated signaling pathways. Bcl-2 homology domain 3-only (BH3) members of the Bcl-2 gene family are of interest as possible initiators of mitochondrial dysfunction and release of apoptogenic molecules after seizures. Previously, we showed expression of the BH3-only protein Bim increased in the rat hippocampus but not neocortex following focal-onset status epilepticus. Here, we examined Bim expression in mice and compared seizure-damage between wild-type and Bim-deficient animals. Status epilepticus induced by intra-amygdala kainic acid caused extensive neuronal death within the ipsilateral hippocampal CA3 region. Hippocampal activation of factors associated with transcriptional and post-translational activation of Bim, including CHOP and c-Jun NH(2)-terminal kinases, was significant within 1 h. Up-regulation of bim mRNA was evident after 2 h and Bim protein was increased from 4-24 h. Hippocampal CA3 neurodegeneration was reduced in Bim-deficient mice compared to wild-type animals following seizures in vivo, and short interfering RNA molecules targeting bim reduced cell death following kainic acid treatment of hippocampal organotypic cultures. In contrast, neocortical Bim expression declined after status epilepticus and neocortex damage in Bim-deficient mice was comparable to wild-type animals. These results demonstrate region-specific differential contributions of Bim to seizure-induced neuronal death. KeywordsApoptosis; Bax; Bcl-2; FKHR; Hippocampus; JNK; Neuroprotection; Temporal lobe epilepsy Signaling pathways associated with the orchestration of apoptosis may contribute to neuronal death after experimental seizures.1 Both caspase-dependent and -independent apoptosis pathways have been implicated. 1 The Bcl-2 gene family are critical upstream regulators of the mitochondrial (intrinsic) apoptotic pathways. 2 Prolonged seizures (status epilepticus), and glutamate excitotoxicity in certain models, cause mitochondrial dysfunction and release of NIH Public Access Author ManuscriptCell Death Differ. Author manuscript; available in PMC 2010 October 6. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript apoptogenic molecules, including cytochrome c ,3 and apoptosis inducing factor (AIF). 4 Support for involvement of Bcl-2 family members comes from several observations. Seizures cause multi-domain pro-apoptotic Bax to cluster around mitochondria at the time of cytochrome c release, 5 and Bax-deficient neurons have been reported to be abnormally resistant to excitotoxicity. 6 Moreover, over-expression of anti-apoptotic Bcl-xl reduces cell death after seizure-like insults in vivo ,7 and, conversely, mice deficient in anti-apoptotic Bcl-w are abnormally vulnerable to hippocampal damage after seizures. 3 However, a functional role for Bax in excitotoxicity has been excluded by some studies. 4 Also, calcium exposure of mitochondria alone, 8 and calpain activity, 9 can trigger release...

Experimentally evoked seizures can activate the intrinsic mitochondrial cell death pathway, components of which are modulated in the hippocampus of patients with temporal lobe epilepsy. Bcl-2 family proteins are critical regulators of mitochondrial dysfunction, but their significance in this setting remains primarily untested. Presently, we investigated the mitochondrial pathway and role of anti-apoptotic Bcl-2 proteins using a mouse model of seizure-induced neuronal death. Status epilepticus was evoked in mice by intra-amygdala kainic acid, causing cytochrome c release, processing of caspases 9 and 7, and death of ipsilateral hippocampal pyramidal neurons. Seizures caused a rapid decline in hippocampal Bcl-w levels not seen for either Bcl-2 or Bcl-xl. To test whether endogenous Bcl-w was functionally significant for neuronal survival, we investigated hippocampal injury after seizures in Bcl-w-deficient mice. Seizures induced significantly more hippocampal CA3 neuronal loss and DNA fragmentation in Bcl-w-deficient mice compared with wild-type mice. Quantitative electroencephalography analysis also revealed that Bcl-w-deficient mice display a neurophysiological phenotype whereby there was earlier polyspike seizure onset. Finally, we detected higher levels of Bcl-w in hippocampus from temporal lobe epilepsy patients compared with autopsy controls. These data identify Bcl-w as an endogenous neuroprotectant that may have seizure

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.

Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30–45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory.