Altered Calcium Channel Currents in Purkinje Cells of the Neurological Mutant Mouseleaner

Abstract

Mutations of the alpha1A 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 of tottering and leaner. The leaner 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 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 alpha1A. In Purkinje cells from normal mice, 82% of the whole-cell 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 properties indistinguishable from that of normal Purkinje neurons. Additionally, the omega-agatoxin-IVA-insensitive current was unaffected in homozygous leaner mice. Thus, the leaner mutation selectively reduces P-type currents in Purkinje cells, and the alpha1A subunit and P-type current appear to be essential for normal cerebellar function.

Familial hemiplegic migraine mutations increase Ca 2+ influx through single human Ca V 2.1 channels and decrease maximal Ca V 2.1 current density in neurons

“…Tg la mutants also showed a slower velocity and frequent failure of propagation of CSD and a much larger reduction of excitatory with respect to inhibitory neurotransmitter release. It has been shown that tg and tg la mutations lead to a decreased P͞Q current density in both native cerebellar neurons and in heterologous expression systems, and that the tg la mutation shifts the activation curve of Ca V 2.1 channels to depolarized voltages and reduces their singlechannel open probability (26)(27)(28). These data support the conclusion that a reduced Ca 2ϩ entry through Ca V 2.1 channels reduces neuronal cortical network excitability and makes the cortex more resistant to CSD.…”

Spinocerebellar Ataxia Type 6 Mutation Alters P-type Calcium Channel Function

“…In addition to SCA6, the ␣1A channel is linked to tottering (tg) and leaner (tg la ) mice. The tg la mice have a severe progressive ataxia, and this mutated channel was reported to exhibit a considerably reduced Ca 2ϩ influx into Purkinje cells (27)(28)(29), whereas tg, which expresses mild phenotype, showed a smaller functional alteration (29). Accordingly, the reduced Ca 2ϩ influx by these mutations may account for their ataxic phenotype.…”

Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca 2+ channel activity and inhibitory synaptic transmission

“…A mutation in the C terminus of mouse ␣ 1A significantly reduces P͞Q-type Ca 2ϩ currents in tg la cerebellar Purkinje cells (27,28), without detectably lowering of ␣ 1A mRNA or protein (29). In mice lacking ␣-neurexin, a functional weakening of N-type Ca 2ϩ channels is observed despite the normal surface abundance of the channel protein (30).…”