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Seizure-induced neuronal death in the immature brain
Claude G Wasterlain1, Jerome Niquet, Kerry W Thompson
1Epilepsy Research Laboratory, VA Greater Los Angeles Healthcare System, Department of Neurology Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA. wasterla@ucla.edu
Insights
The developing brain
Area of Science:
- Neuroscience
- Developmental Biology
- Epileptology
Background:
- The developing brain exhibits age-specific responses to epileptic seizures and status epilepticus.
- Neonatal brains tolerate seizures better due to lower metabolic rates, but severe seizures can impair growth and alter neuronal circuits.
- Post-infancy, the developing brain's high metabolic rate and complex networks make it vulnerable to excitotoxicity during seizures.
Purpose of the Study:
- To investigate the age- and model-dependent outcomes of seizures and status epilepticus in the developing brain.
- To understand the mechanisms of cell death, including necrosis and apoptosis, following seizures in different age groups.
- To demonstrate seizure-induced epileptogenesis in the developing brain using reliable animal models.
Main Methods:
- Utilizing experimental animal models to study seizure responses in the developing brain across different age groups.
- Analyzing neuronal damage, behavioral deficits, and the development of chronic epilepsy.
- Investigating biochemical pathways of cell death, including mitochondrial cytochrome release and caspase activation.
Main Results:
- Seizure outcomes are highly dependent on the age of the developing brain and the specific experimental model used.
- Status epilepticus can lead to neuronal death, behavioral deficits, and chronic epilepsy in some models, but minimal damage in others.
- Established models demonstrate that seizures can induce epileptogenesis in the developing brain, leading to spontaneous seizures and chronic epilepsy.
Conclusions:
- The developing brain's response to seizures and status epilepticus is complex and varies significantly with age and model.
- Apoptosis is more prevalent in younger brains, while necrosis, sharing features with apoptosis, occurs in adults and is linked to energy failure.
- Seizure-induced epileptogenesis is a demonstrable phenomenon in the developing brain, with long-term consequences being age- and model-dependent.
Abstract:
The response of the developing brain to epileptic seizures and to status epilepticus is highly age-specific. Neonates with their low cerebral metabolic rate and fragmentary neuronal networks can tolerate relatively prolonged seizures without suffering massive cell death, but severe seizures in experimental animals inhibit brain growth, modify neuronal circuits, and can lead to behavioral deficits and to increases in neuronal excitability. Past infancy, the developing brain is characterized by high metabolic rate, exuberant neuronal and synaptic networks and overexpression of receptors and enzymes involved in excitotxic mechanisms. The outcome of seizures is highly model-dependent. Status epilepticus may produce massive neuronal death, behavioral deficits, synaptic reorganization and chronic epilepsy in some models, little damage in others. Long-term consequences are also highly age- and model-dependent. However, we now have some models which reliably lead to spontaneous seizures and chronic epilepsy in the vast majority of animals, demonstrating that seizure-induced epileptogenesis can occur in the developing brain. The mode cell death from status epilepticus is largely (but not exclusively) necrotic in adults, while the incidence of apoptosis increases at younger ages. Seizure-induced necrosis has many of the biochemical features of apoptosis, with early cytochrome release from mitochondria and capase activation. We speculate that this form of necrosis is associated with seizure-induced energy failure.
