Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus

Abstract

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...

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

“…Hippocampal neurons are also protected in in vitro models of KA-and N-methyl-Daspartate-induced excitotoxicity (Concannon et al, 2010;Murphy et al, 2010). The neocortex was not spared in bim À/À mice, consistent with the lack of its induction in that brain region after seizures (Murphy et al, 2010). Also, Theofilas et al (2009) found bim À/À mice were not protected against neuronal death in an in vivo model of excitotoxicity.…”

“…Analysis of hippocampal damage 3 days after status epilepticus revealed a modest but nevertheless significant reduction in neuronal death in bim À/À mice compared with wild-type animals. Hippocampal neurons are also protected in in vitro models of KA-and N-methyl-Daspartate-induced excitotoxicity (Concannon et al, 2010;Murphy et al, 2010). The neocortex was not spared in bim À/À mice, consistent with the lack of its induction in that brain region after seizures (Murphy et al, 2010).…”

“…Prolonged seizures evoked by intraamygdala KA upregulate Bim protein levels in the hippocampus of rats and mice (Murphy et al, 2010). The upregulation of Bim is JNK dependent in mice since it is blocked by SP600125 (Murphy et al, 2010), although FoxO1 or 3a may also be important (Murphy et al, 2010;Shinoda et al, 2004).…”

Chopping Out CHOP Chops the Fate of Neurons

“…That said, CHOP was shown to promote neuronal survival after endoplasmic reticulum stress, supporting a neuroprotective role of CHOP (8). Since CHOP expression in the hippocampus is induced by seizures (9), the question arises whether this increase promotes neuronal cell death in epilepsy or whether an increase in CHOP is an adaptive response to limit neuronal cell loss. The distinction between those possibilities is of obvious relevance for the development of neuroprotective strategies in epilepsy.…”

Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus

“…Thus, a large number of studies have been conducted to identify the potential biochemical pathways involved in KA-induced apoptosis, such as oxidative stress, cell cycle re-entry and calpain/cdk5 activation [8,[10][11][12][13][14][15][16]. Programmed cell death is primarily mediated by the extrinsic or death receptor pathway, and the intrinsic or mitochondrial pathway, which converge to activate mitochondria [17,18].…”