Abstract

Mutations of the α_1A calcium channel subunit have been shown to cause such human neurological diseases as familial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6 and also to cause the murine neurological phenotypes oftottering and leaner. Theleaner phenotype is recessive and characterized by ataxia with cortical spike and wave discharges (similar to absence epilepsy in humans) and a gradual degeneration of cerebellar Purkinje and granule cells. The mutation responsible is a single-base substitution that produces truncation of the normal open reading frame beyond repeat IV and expression of a novel C-terminal sequence. Here, we have used whole-cell recordings to determine whether theleaner mutation alters calcium channel currents in cerebellar Purkinje cells, both because these cells are profoundly affected in leaner mice and because they normally express high levels of α_1A. In Purkinje cells from normal mice, 82% of the whole-cell current was blocked by 100 nmω-agatoxin-IVA. In Purkinje cells from homozygousleaner mice, this ω-agatoxin-IVA-sensitive current was 65% smaller than in control cells. Although attenuated, the ω-agatoxin-IVA-sensitive current in homozygous leanercells had properties indistinguishable from that of normal Purkinje neurons. Additionally, the ω-agatoxin-IVA-insensitive current was unaffected in homozygous leaner mice. Thus, theleaner mutation selectively reduces P-type currents in Purkinje cells, and the α_1A subunit and P-type current appear to be essential for normal cerebellar function.