The long-term objective of this research is to elucidate the neurochemical substrates of the epileptic state.
A specific aim i s to distinguish innate neurochemical changes associated with seizure susceptibility from changes occurring as a consequence of repeated seizure activity. This is an important problem in epilepsy research that has never been clearly resolved. A solution to this problem will be sought using the epilepsy or E1 mouse. The dominantly expressed E1 mutation produces a convulsive disorder that is best characterized as complex partial seizures with secondary generalization. A C56BL/6 (B6) strain congenic for the E1 gene, i.e., B6.E1, was produced for these studies by selectively transferring the E1 gene from the E1 strain to the B6 strain. This has significantly enhanced the usefulness of these mice as an animal model of epilepsy because inbred B6 mice can now serve as genetic controls. Any differences found between the B6 and B6.E1 congenic mice will likely result from the effects of the E1 gene. The B6, E1 and B6.E1 mice will be used to study the influence of the E1 gene on the distribution of total lipids (including gangliosides) in the cerebral cortex, hippocampus, brain stem, and cerebellum. In addition, the specific activities of the total, Mg2+, Na+-K+ and Ca2+ ATPase will be studied in homogenates of these brain regions and in microsomes, synaptosomes, and mitochondria prepared from cerebral cortex. The high affinity (Ca2+ + Mg2+) ATPase will also be studied in the synaptosomal fraction. Because little is known about the role of myelin in epilepsy, total lipids and Na+, K+ ATPase activity will also be analyzed in purified myelin preparations. The above neurochemical traits were chosen because of their reported or potential involvement in epilepsy. These traits will be compared between the seizure-resistant B6 mice, and three groups of E1 and B6.E1 mice: (1) those not having seizures, 2) those having 16 seizures, 3) those having 30 seizures. Differences found between the mice in the first group can be attributed to either genetic background or expression of E1, whereas differences found in the second and third groups can be attributed to repeated seizure activity. This paradigm will allow us to determine, for the first time, whether specific neurochemical changes are related to the cause of seizures or are related to the effects of seizures.
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