| Epilepsy is defined by recurrent synchronized discharges that interrupt the otherwise normal function of neuronal circuits. Approximately 1% of the population suffers from some form of epilepsy, which can vary in onset, severity, and etiology. However, the spectrum of epilepsies occurring in childhood is broader than at any other age. They range from relatively infrequent benign febrile seizures to constant permanently disabling conditions. One specific form of epilepsy, referred to as absence or petit-mal, typically present during childhood and are defined as a paroxysmal loss of consciousness, of abrupt and sudden onset, accompanied by an EEG profile of bilateral spike-and-wave discharges.; Animal models of inherited epilepsy offer tremendous potential for identifying genes and cellular mechanisms related to human epileptic disorders. They also provide an invaluable resource for studying other aspects of epilepsy such as the progression of seizure activity, associated biochemical and neurological changes, and the pharmacology and testing of antiepileptic drugs. Our studies involved to well characterized mouse models for absence: the tottering mouse and the lethargic mouse.; We utilized positional cloning strategies in an attempt to identify the genes responsible for absence epilepsy in these mice. Positional cloning is a genome-based approach to gene identification which utilizes meiotic linkage mapping to localize genes and then isolate the genes by isolating regional cloned DNA. To this end, we were successful in identifying the voltage sensitive calcium channel of the a 1A subtype, Cacna1a, that is mutated in tottering mice. A comparison is made of the different mouse mutations to the mutations in the human homolog of this gene. In addition, we speculate that the cause of epilepsy in tottering mice is due to a decrease in calcium conductance of the P- and Q-type channels encoded by the Cacna1a gene. The data presented in this dissertation identifies the first gene involved in absence epilepsy and defines a trigger for seizure generation. |
