Tottering Mouse

The tottering mouse (tg/tg) results from a mutation in the gene that encodes for the Cav2.1 (P/Q-type) Ca²⁺ channel and is a model for the Cav2.1 channelopathy, episodic ataxia type 2 (EA2). EA2 patients suffer from periods of transient cerebellar dysfunction and other neurological deficits. The tg/tg mouse has a behavioral phenotype of episodic motor attacks, absence seizures, and mild ataxia. The cerebellum plays an essential role in the episodic dystonia, and numerous episodic symptoms can be triggered by stress, ethanol, and caffeine in both EA2 patients and tg/tg. While linked to mobilization of intracellular Ca2+ stores, how these triggers act to initiate the motor attacks is unknown. The morphological changes in tg/tg are rather modest, most notably an increase in noradrenergic innervation by the locus coeruleus. There is an upregulation of L-type Ca2+ channels in tg/tg that is strongly implicated in the episodic dystonia. The P/Q-type channel is expressed heavily in the cerebellum and widely involved with presynaptic neurotransmitter release in the nervous system. The mutation affects the pore-lining region of the P/Q-type channel and leads to a reduction in channel function. Synaptic transmission is reduced at several synapses, including the parallel fiber-Purkinje cell synapse. However, at many synapses compensation for the loss of P/Q-type channels by other voltage-gated Ca²⁺ channels mitigates the deficits in synaptic transmission in tg/tg. Irregular Purkinje cell simple spike firing is linked to Ca2+-activated K+ channels and the behavioral abnormalities. The recent observation of transient low-frequency oscillations in the cerebellum and cerebral cortex may provide a mechanism for the paroxysmal motor attacks. These oscillations are intrinsically generated, coupled to the episodic dystonia, and linked to the upregulation of L-type channels. Although much remains to be understood, the tg/tg mouse continues to be a highly useful murine model of a Cav2.1 channelopathy and episodic neurologic dysfunction.