B&A Therapeutics, Ben-Ari Institute of Neuroarcheology, Batiment Beret-Delaage, zone Luminy entreprises, 13288, Marseille, Cedex 09, France.
Neurochlore, Ben-Ari Institute of Neuroarcheology, Batiment Beret-Delaage, Zone Luminy Biotech Entreprises, 13288, Marseille, Cedex 09, France.
Nat Commun. 2018 Apr 12;9(1):1422. doi: 10.1038/s41467-018-03802-y.
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] 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] 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] levels and GABAergic inhibition.
我们报告说，一半纹状体胆碱能中间神经元是具有双重递质的胆碱能和 GABA 能中间神经元 (CGINs)，表达 ChAT、GAD65、Lhx7 和 Lhx6 mRNA，用 GAD 和 VGAT 标记，产生单突触双重胆碱能/GABA 能电流和抑制性暂停反应。多巴胺剥夺增加 CGINs 的持续活动，并由于高 [Cl] 水平而消除 GABA 抑制，包括皮质纹状体暂停。多巴胺剥夺还显著增加 CGINs 的树突枝和单突触连接的概率，表明形成了一个密集的 CGINs 网络。 NKCC1 氯离子转运体抑制剂布美他尼降低 [Cl] 水平，恢复 GABA 能抑制、皮质纹状体暂停-反弹反应，并减轻多巴胺剥夺的运动效应。因此，纹状体胆碱能兴奋性驱动的大部分被伴随的强大 GABA 能抑制所平衡，而多巴胺剥夺会损害这种抑制。布美他尼对帕金森病主要特征的抑制为基于恢复低 [Cl] 水平和 GABA 能抑制的新型治疗策略铺平了道路。
