Mutations in several genes have been linked to some types of epilepsy. Several genes that code for protein subunits of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes. Several ligand-gated ion channels have been linked to some types of frontal and generalized epilepsies. One speculated mechanism for some forms of inherited epilepsy are mutations of the genes which code for sodium channel proteins; these defective sodium channels stay open for too long thus making the neuron hyper-excitable. Glutamate, an excitatory neurotransmitter, may thereby be released from these neurons in large amounts which—by binding with nearby glumtamanergic neurons—triggers excessive CA++ release in these post-synaptic cells. Such excessive calcium release can be neurotoxic to the affected cell. The hippocampus, which contains a large volume of just such glutamanergic neurons (and NMDA receptors, which are permeable to CA++ entry after binding of both sodium and glutamate), is especially vulnerable to epileptic seizure, subsequent spread of excitation, and possible neuronal death. Another possible mechanism involves mutations leading to ineffective GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related mutations in some non-ion channel genes have also been identified.
Epileptogenesis is the process by which a normal brain develops epilepsy after an insult. One interesting finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold." This phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire) was discovered by Dr. Graham Goddard in 1967. Chemical stimulation can also induce seizures; repeated exposures to some pesticides have been shown to induce seizures in both humans and animals. One mechanism proposed for this is called excitotoxicity. The roles of kindling and excitotoxicity, if any, in human epilepsy are currently hotly debated.
Other causes of epilepsy are brain lesions, where there is scar tissue or another abnormal mass of tissue in an area of the brain.
The complexity of understanding what seizures are have led to considerable efforts to use computational models of epilepsy to both interpret experimental and clinical data, as well as guide strategies for therapy.
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