We are using classical mouse neurological mutations [tottering (tg), nervous (nr), meandner tail (mea)] that affect the cerebellum, combined with reverse genetics, as a model system for understanding the cellular and molecular mechanisms that guide development of the mammalian brain. The tg mice were chosen for study because they are one of the few mouse models for absence epilepsy. Although half of all human epilepsies have a genetic component, and as much as 1% of the population suffers from epilepsy, no genes had been identified for absence epilepsy. By positional cloning, we showed that tg encodes the Cacnl1a4 voltage-sensitive calcium channel. Contemporaneously, mutations in human CACNL1A4 were found in patients with episodic ataxia 2 (EA2) and familial hemiplegic migraine (FHM). Future studies are aimed at understanding the pathophysiology of these diseases. nr mice were chosen for study because they have an unusual pathology that initially includes rounding and clumping of the mitochondria and a disruption in the organization of the ER and Golgi in cerebellar Purkinje neurons. Subsequently, nr Purkinje cells degenerate in a striped pattern that is the mirror image of the Purkinje cell degeneration found in tg mice carrying the leaner allele. Positional cloning experiments are currently underway to identify the gene encoded by the nr locus. mea mice were chosen because they have a morphogenetic defect that appears to define a discrete compartment of the cerebellum that has not been previously defined by histological or functional criteria. Future studies are aimed at positionally cloning the mea gene product.
