Tottering mouse

Abstract

The tottering (tg/tg) mouse is due to a mutation in the gene that encodes for the Cav2.1 (P/Q-type) Ca2+ channel. The tg/tg mouse 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. The paroxysmal motor dysfunction is triggered by stress, ethanol, and caffeine in both EA2 patients and the tg/tg mouse. How stress, caffeine, or ethanol acts to initiate the motor attacks is unknown. The morphological changes in the tg/tg mouse are rather modest. There is an upregulation of L-type Ca2+ channels in the tg/tg mouse that is strongly implicated in the episodic dystonia. An increase in noradrenergic innervation by the locus coeruleus does not appear to be involved in the episodic motor phenotype. The mutation affects the pore lining region of the P/Q-type Ca2+ channel and leads to a reduction in channel function. The P/Q-type channel is expressed heavily in the cerebellum and widely involved with presynaptic neurotransmitter release in the nervous system. At several synapses the dependence of synaptic transmission on P/Q-type Ca2+ channels is reduced, 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 the tg/tg mouse. Purkinje cell simple spike firing is irregular and is linked to calcium-activated potassium channels and the behavioral abnormalities. The recent observation of low frequency oscillations in the cerebellum may provide a mechanism for the paroxysmal motor attacks. These oscillations are intrinsic to the cerebellum, are coupled to the episodic dystonia, and involve the upregulation of L-type Ca2+ channels. Although much remains to be understood, the tg/tg mouse continues to be a highly useful mouse model of a Cav2.1 channelopathy.