RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2.
Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while β-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress-induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease.
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.
Julie
J
Salvi
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.
Federica
F
Bertaso
Institut des Neurosciences de Montpellier, INSERM U844, Hôpital Saint Eloi, Bâtiment 80, rue Augustin Fliche, BP74103, 34091 Montpellier cedex 05, France.
Anne-Laure
AL
Mausset-Bonnefont
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.
Alexandra
A
Metz
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Plateforme de Vectorologie de Montpellier (PVM), Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.
Céline
C
Lemmers
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.
Fabrice
F
Ango
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.
Laurent
L
Fagni
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France. Electronic address: philippe.lory@igf.cnrs.fr.
Philippe
P
Lory
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France; Labex ICST Institut de Génomique Fonctionnelle, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France. Electronic address: alexandre.mezghrani@igf.cnrs.fr.
Alexandre
A
Mezghrani
D000818:Animals; D001259:Ataxia / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009068:Movement / Q000502:physiology; D009759:Nystagmus, Pathologic / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004856:Postural Balance / Q000235:genetics; D011689:Purkinje Cells / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic
D020864:Calcium Channels, N-Type; D049452:Green Fluorescent Proteins; D034741:RNA, Small Interfering
Acetazolamide; Ataxia; Cerebellum; Mouse; P/Q-type calcium channel; Purkinje neuron; RNA interference