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Nat Commun. 2018 Apr 12;9(1):1422. doi: 10.1038/s41467-018-03802-y.

GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease.

Author information

1
B&A Therapeutics, Ben-Ari Institute of Neuroarcheology, Batiment Beret-Delaage, zone Luminy entreprises, 13288, Marseille, Cedex 09, France.
2
Neurochlore, Ben-Ari Institute of Neuroarcheology, Batiment Beret-Delaage, Zone Luminy Biotech Entreprises, 13288, Marseille, Cedex 09, France.
3
INMED, INSERM U901 and Aix-Marseille University, 13273, Marseille, Cedex 09, France.
4
B&A Therapeutics, Ben-Ari Institute of Neuroarcheology, Batiment Beret-Delaage, zone Luminy entreprises, 13288, Marseille, Cedex 09, France. ben-ari@batherapeutics.com.
5
Neurochlore, Ben-Ari Institute of Neuroarcheology, Batiment Beret-Delaage, Zone Luminy Biotech Entreprises, 13288, Marseille, Cedex 09, France. ben-ari@batherapeutics.com.

Abstract

We report that half striatal cholinergic interneurons are dual transmitter cholinergic and GABAergic interneurons (CGINs) expressing ChAT, GAD65, Lhx7, and Lhx6 mRNAs, labeled with GAD and VGAT, generating monosynaptic dual cholinergic/GABAergic currents and an inhibitory pause response. Dopamine deprivation increases CGINs ongoing activity and abolishes GABAergic inhibition including the cortico-striatal pause because of high [Cl-]i levels. Dopamine deprivation also dramatically increases CGINs dendritic arbors and monosynaptic interconnections probability, suggesting the formation of a dense CGINs network. The NKCC1 chloride importer antagonist bumetanide, which reduces [Cl-]i levels, restores GABAergic inhibition, the cortico-striatal pause-rebound response, and attenuates motor effects of dopamine deprivation. Therefore, most of the striatal cholinergic excitatory drive is balanced by a concomitant powerful GABAergic inhibition that is impaired by dopamine deprivation. The attenuation by bumetanide of cardinal features of Parkinson's disease paves the way to a novel therapeutic strategy based on a restoration of low [Cl-]i levels and GABAergic inhibition.

PMID:
29651049
PMCID:
PMC5897332
DOI:
10.1038/s41467-018-03802-y
[Indexed for MEDLINE]
Free PMC Article

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