Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission,and progressive ataxia in mice lacking the alpha(1A)-subunit

The Ca2+ channel alpha(1A)-subunit is a voltage-gated, pore-forming membran e protein positioned at the intersection of two important lines of research : one exploring the diversity of Ca2+ channels and their physiological role s, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and mig raine. alpha(1A)-Subunits are thought to support both P- and Q-type Ca2+ ch annel currents, but the most direct test, a null mutant, has not been descr ibed, nor is it known which changes in neurotransmission might arise from e limination of the predominant Ca2+ delivery system at excitatory nerve term inals. We generated alpha(1A)-deficient mice (alpha(1A)(-/-)) and found tha t they developed a rapidly progressive neurological deficit with specific c haracteristics of ataxia and dystonia before dying approximate to 3-4 weeks after birth. P-type currents in Purkinje neurons and P- and Q-type current s in cerebellar granule cells were eliminated completely whereas other Ca2 channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in al pha(1A)(-/-) hippocampal slices persisted despite the lack of P/Q-type chan nels but showed enhanced reliance on N-type and R-type Ca2+ entry. The alph a(1A)(-/-) mice provide a starting point for unraveling neuropathological m echanisms of human diseases generated by mutations in alpha(1A).