Format

Send to

Choose Destination
Neurobiol Dis. 2014 Aug;68:47-56. doi: 10.1016/j.nbd.2014.04.005. Epub 2014 Apr 21.

RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2.

Author information

1
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.
2
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université Montpellier I & II, 141, rue de la Cardonille, 34094 Montpellier cedex 05, France.
3
Institut des Neurosciences de Montpellier, INSERM U844, Hôpital Saint Eloi, Bâtiment 80, rue Augustin Fliche, BP74103, 34091 Montpellier cedex 05, France.
4
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.
5
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.
6
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.

Abstract

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.

KEYWORDS:

Acetazolamide; Ataxia; Cerebellum; Mouse; P/Q-type calcium channel; Purkinje neuron; RNA interference

PMID:
24768804
DOI:
10.1016/j.nbd.2014.04.005
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center