Ablation of P/Q-type Ca 2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α 1A -subunit

Abstract

The Ca 2+ channel α 1A -subunit is a voltage-gated, pore-forming membrane protein positioned at the intersection of two important lines of research: one exploring the diversity of Ca 2+ channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. α 1A -Subunits are thought to support both P- and Q-type Ca 2+ channel currents, but the most direct test, a null mutant, has not been described, nor is it known which changes in neurotransmission might arise from elimination of the predominant Ca 2+ delivery system at excitatory nerve terminals. We generated α 1A -deficient mice (α 1A −/− ) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying ≈3–4 weeks after birth. P-type currents in Purkinje neurons and P- and Q-type currents in cerebellar granule cells were eliminated completely whereas other Ca 2+ channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in α 1A −/− hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca 2+ entry. The α 1A −/− mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in α 1A .