Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice

Mutations in the CACNA1A gene are associated with neurological disorders, such as ataxia, hemiplegic migraine, and epilepsy. These mutations affect the pore-forming α(1A)-subunit of Ca(V)2.1 channels and thereby either decrease or increase neuronal Ca(2+) influx. A decreased Ca(V)2.1-mediated Ca(2+)...

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Bibliographic Details
Published in:	The Journal of neuroscience 2012-10, Vol.32 (44), p.15533
Main Authors:	Gao, Zhenyu, Todorov, Boyan, Barrett, Curtis F, van Dorp, Stijn, Ferrari, Michel D, van den Maagdenberg, Arn M J M, De Zeeuw, Chris I, Hoebeek, Freek E
Format:	Article
Language:	eng
Subjects:	Action Potentials - drug effects Action Potentials - physiology Animals Behavior, Animal - physiology Benzimidazoles - pharmacology Calcium - physiology Calcium Channels, N-Type - drug effects Calcium Channels, N-Type - genetics Calcium Channels, N-Type - physiology Calcium Channels, P-Type - genetics Calcium Channels, Q-Type - genetics Calcium Signaling - drug effects Cerebellar Ataxia - drug therapy Cerebellar Ataxia - genetics Cerebellar Ataxia - psychology Chlorzoxazone - therapeutic use Extracellular Space - physiology Female Homeostasis - physiology Male Mice Muscle Relaxants, Central - pharmacology Mutation - genetics Mutation - physiology Patch-Clamp Techniques Potassium Channels, Calcium-Activated - agonists Psychomotor Performance - physiology Purkinje Cells - physiology
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Summary:	Mutations in the CACNA1A gene are associated with neurological disorders, such as ataxia, hemiplegic migraine, and epilepsy. These mutations affect the pore-forming α(1A)-subunit of Ca(V)2.1 channels and thereby either decrease or increase neuronal Ca(2+) influx. A decreased Ca(V)2.1-mediated Ca(2+) influx has been shown to reduce the regularity of cerebellar Purkinje cell activity and to induce episodic cerebellar ataxia. However, little is known about how ataxia can be caused by CACNA1A mutations that increase the Ca(2+) influx, such as the S218L missense mutation. Here, we demonstrate that the S218L mutation causes a negative shift of voltage dependence of Ca(V)2.1 channels of mouse Purkinje cells and results in lowered thresholds for somatic action potentials and dendritic Ca(2+) spikes and in disrupted firing patterns. The hyperexcitability of Cacna1a(S218L) Purkinje cells was counteracted by application of the activators of Ca(2+)-dependent K(+) channels, 1-EBIO and chlorzoxazone (CHZ). Moreover, 1-EBIO also alleviated the irregularity of Purkinje cell firing both in vitro and in vivo, while CHZ improved the irregularity of Purkinje cell firing in vitro as well as the motor performance of Cacna1a(S218L) mutant mice. The current data suggest that abnormalities in Purkinje cell firing contributes to cerebellar ataxia induced by the S218L mutation and they advocate a general therapeutic approach in that targeting Ca(2+)-dependent K(+) channels may be beneficial for treating ataxia not only in patients suffering from a decreased Ca(2+) influx, but also in those suffering from an increased Ca(2+) influx in their Purkinje cells.
ISSN:	1529-2401