The Tottering Mouse

In the late 1950s, a novel spontaneous mutation was found in the same litter of mice while breeding by Green and Sidman at the Roscoe B. Jackson Memorial Laboratory in Maine. Mice harboring this mutation, which was found to be recessive, were termed tottering (tg/tg) mice, and exhibited a series of neurological abnormalities, including a paroxysmal motor disturbances (dyskinesia/dystonia), a wobbly ataxic gait, and absence seizures. Since the initial discovery of this mutation, numerous studies have investigated the underlying genetics and behavioral consequences in the tg/tg mouse, and this mouse has proven useful in our understanding of several episodic neurological disorders involving the cerebellum. Caused by a mutation in the Cacna1a gene that encodes the P/Q-type voltage-gated Ca2+ channel, the tg/tg mouse is a model for the human disorder episodic ataxia type 2 (EA2) and has provided insights into the mechanisms of episodic cerebellar dysfunction.