Neurogenic function in rats with unilateral hippocampal sclerosis that experienced early-life status epilepticus.

Status epilepticus in the adult brain invariably causes an increase in hippocampal neurogenesis and the appearance of ectopic cells and this has been implicated as a causal factor in epileptogenesis. The effect of status epilepticus on neurogenesis in the developing brain is less well characterized and models of early-life seizures typically do not reproduce the hippocampal damage common to human mesial temporal sclerosis. We recently reported that evoking status epilepticus by intra-amygdala microinjection of kainic acid in post-natal (P) day 10 rats caused substantial acute neuronal death within the ipsilateral hippocampus and rats later developed unilateral hippocampal sclerosis and spontaneous recurrent seizures.

Experimental neonatal status epilepticus and the development of temporal lobe epilepsy with unilateral hippocampal sclerosis.

Hippocampal sclerosis is a common pathological finding in patients with temporal lobe epilepsy, including children, but a causal relationship to early-life seizures remains in question. Neonatal status epilepticus in animals can result in neuronal death within the hippocampus, although macroscopic features of hippocampal shrinkage are not evident at adulthood. Here, we examined electrophysiological and pathological consequences of focally evoked status epilepticus triggered by intra-amygdala microinjection of kainic acid in postnatal day 10 rat pups.

Bcl-w protects hippocampus during experimental status epilepticus.

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.

Expression, interaction, and proteolysis of death-associated protein kinase and p53 within vulnerable and resistant hippocampal subfields following seizures.

Death-associated protein (DAP) kinase is a novel regulator of cell death whose in vivo target(s) and role in neuronal cell death remain uncertain. Since DAP kinase has been implicated in p53-mediated apoptosis, a pathway activated following epileptic brain injury, we examined the relationship between DAP kinase and p53 following seizures. Rats underwent brief (40-min) seizures evoked by intraamygdala kainic acid, which caused the death of ipsilateral CA3 neurons while preserving the contralateral CA3 subfield.

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.

Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy.

Development of a model of seizure-induced hippocampal injury with features of programmed cell death in the BALB/c mouse.

Although mice are amenable to gene knockout, they have not been exploited in the setting of seizure-induced neurodegeneration due to the resistance to injury of key mouse strains. We refined and developed models of seizure-induced neuronal death in the C57BL/6 and BALB/c strains by focally evoking seizures using intra-amygdala kainic acid. Seizures in adult male BALB/c mice, or C57BL/6 mice as reference, caused ipsilateral death of CA1 and CA3 neurons within the hippocampus.

Subcellular distribution of Bcl-2 family proteins and 14-3-3 within the hippocampus during seizure-induced neuronal death in the rat.

The molecular regulation of seizure-induced neuronal death may involve interactions between proteins of the Bcl-2 and 14-3-3 families. To further examine these pathways we performed subcellular fractionation on hippocampi obtained following a brief period of status epilepticus in the rat. Western blotting determined seizures induced caspase-8 cleavage and increased Bcl-w levels within the cytoplasm.

Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures.

Death-associated protein (DAP) kinase is calcium-regulated and known to function downstream of death receptors, prompting us to examine its role in the mechanism of seizure-induced neuronal death. Brief seizures were focally evoked in rats, eliciting neuronal death within the CA3 subfield of the hippocampus, and to a lesser extent, cortex. Western blotting confirmed expression of DAP kinase within hippocampus and cortex at the predicted weight of approximately 160 kDa.

Interaction of 14-3-3 with Bid during seizure-induced neuronal death.

Seizure-induced neuronal death may involve coordinated intracellular trafficking and protein-protein interactions of members of the Bcl-2 family. The 14-3-3 proteins are known to sequester certain pro-apoptotic members of this family. BH3-interacting domain death agonist (Bid) may contribute to seizure-induced neuronal death, although regulation by 14-3-3 has not been reported.

Formation of a tumour necrosis factor receptor 1 molecular scaffolding complex and activation of apoptosis signal-regulating kinase 1 during seizure-induced neuronal death.

The consequences of activation of tumour necrosis factor receptor 1 (TNFR1) during neuronal injury remain controversial. The apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase, can mediate cell death downstream of TNFR1. Presently, we examined the formation of the TNFR1 signalling cascade and response of ASK1 during seizure-induced neuronal death.