Chapter 52 - Mouse Models of Episodic Ataxia Type 2

Abstract

Episodic ataxia type 2 (EA2) is a disorder characterized by acute attacks of ataxia precipitated by stress, ethanol, and caffeine. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1 pore-forming subunit of the Cav2.1 (P/Q-type) voltage-gated calcium channel. Several mouse strains, including tottering mice, carry loss-of-function mutations in the Cacna1a gene and have been used to investigate the pathomechanisms of EA2. Like EA2 patients, tottering mice exhibit attacks of motor dysfunction triggered by stress, ethanol, and caffeine. The cerebellum and specifically cerebellar Purkinje cells are implicated in tottering mouse attacks. Like EA2 patients, drugs that restore Purkinje cell pacemaking, such as 4-aminopyradine, block tottering attacks. Other mouse strains, such as rocker, leaner, and engineered strains, display a range of phenotypes, from mild, paroxysmal motor dysfunction to chronic dystonia, similar to the range of neurological problems exhibited by EA2 patients. Cacna1a mutant mice have provided insights into the neurobiology of EA2 and into the mechanisms underlying treatments and may, therefore, prove useful for developing novel and more efficacious therapeutics.