title: Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice.
abstract: 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.
authors.affiliation: Department of Neuroscience, Erasmus Medical Centre, 3000 CA Rotterdam, The Netherlands.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Gao
authors.forename: Boyan
authors.initials: B
authors.lastname: Todorov
authors.forename: Curtis F
authors.initials: CF
authors.lastname: Barrett
authors.forename: Stijn
authors.initials: S
authors.lastname: van Dorp
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.forename: Freek E
authors.initials: FE
authors.lastname: Hoebeek
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020865:Calcium Channels, P-Type / Q000235:genetics*; D020907:Calcium Channels, Q-Type / Q000235:genetics*; D020013:Calcium Signaling / Q000187:drug effects; D002524:Cerebellar Ataxia / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology; D002753:Chlorzoxazone / Q000627:therapeutic use; D005110:Extracellular Space / Q000502:physiology; D005260:Female; D006706:Homeostasis / Q000502:physiology; D008297:Male; D051379:Mice; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009154:Mutation / Q000235:genetics / Q000502:physiology; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists*; D011597:Psychomotor Performance / Q000502:physiology; D011689:Purkinje Cells / Q000502:physiology
chemical_list: D001562:Benzimidazoles; D002118:Calcium; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002753:Chlorzoxazone; D009125:Muscle Relaxants, Central; D024681:Potassium Channels, Calcium-Activated; C102635:1-ethyl-2-benzimidazolinone