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

N. Lozovaya , S. Eftekhari , R. Cloarec , L. A Gouty-Colomer , A. Dufour (1) , B. Riffault , M. Billon-Grand , A. Pons-Bennaceur , N. Oumar , N. Burnashev (2) , Y. Ben-Ari (2) , C. Hammond (2)

1 ISARA-Lyon
2 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]

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.

Keywords: Cellular neuroscience; Parkinson's disease

Domains: Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]

N. Lozovaya, S. Eftekhari, R. Cloarec, L. A Gouty-Colomer, A. Dufour, et al.. GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease. Nature Communications, 2018, 9 (1), ⟨10.1038/s41467-018-03802-y⟩. ⟨hal-01963841⟩