ALTERED CALCIUM-CHANNEL CURRENTS IN PURKINJE-CELLS OF THE NEUROLOGICAL MUTANT MOUSE LEANER

Mutations of the alpha(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 th e murine neurological phenotypes of tottering and leaner. The leaner p henotype is recessive and characterized by ataxia with cortical spike and wave discharges (similar to absence epilepsy in humans) and a grad ual degeneration of cerebellar Purkinje and granule cells. The mutatio n responsible is a single-base substitution that produces truncation o f the normal open reading frame beyond repeat IV and expression of a n ovel C-terminal sequence. Here, we have used whole-cell recordings to determine whether the leaner 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 alpha(1A). In Purkinje cells from normal mice, 82% of the whole-cel l current was blocked by 100 nM omega-agatoxin-IVA. In Purkinje cells from homozygous leaner mice, this omega-agatoxin-IVA-sensitive current was 65% smaller than in control cells. Although attenuated, the omega -agatoxin-IVA-sensitive current in homozygous leaner cells had propert ies indistinguishable from that of normal Purkinje neurons. Additional ly, the omega-agatoxin-IVA-insensitive current was unaffected in homoz ygous leaner mice. Thus, the leaner mutation selectively reduces P-typ e currents in Purkinje cells, and the alpha(1A) subunit and P-type cur rent appear to be essential for normal cerebellar function.