Rubi Lena, Fritschy Jean-Marc
University of Zurich, Institute of Pharmacology and Toxicology, Zurich, Switzerland.
Neuroscience Center Zurich, Zurich, Switzerland.
J Neurophysiol. 2020 Apr 1;123(4):1496-1503. doi: 10.1152/jn.00059.2020. Epub 2020 Mar 11.
As the main input nucleus of the basal ganglia, the striatum plays a central role in planning, control, and execution of movement and motor skill learning. More than 90% of striatal neurons, so-called medium spiny neurons (MSN), are GABAergic projection neurons, innervating primarily the substantia nigra pars reticulata or the globus pallidus internus. The remaining neurons are GABAergic and cholinergic interneurons, synchronizing and controlling striatal output by reciprocal connections with MSN. Besides prominent local cholinergic influence, striatal function is globally regulated by dopamine (DA) from the nigrostriatal pathway. Little is known about whether DA depletion, as occurs in Parkinson's disease, affects the activity of striatal interneurons. Here we focused on neuropeptide Y (NPY)-expressing interneurons, which are among the major subgroups of GABAergic interneurons in the striatum. We investigated the effects of striatal DA depletion on GABAergic transmission in NPY interneurons by electrophysiologically recording GABAergic spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs) in identified NPY interneurons in slices from 6-hydroxydopamine (6-OHDA)- and vehicle-injected transgenic NPY-humanized green fluorescent protein (hrGFP) mice with the whole cell patch-clamp technique. We report a significant increase in sIPSC and mIPSC frequency as well as the occurrence of giant synaptic and burst sIPSCs in the 6-OHDA group, suggesting changes in GABAergic circuit activity and synaptic transmission. IPSC kinetics remained unchanged, pointing to mainly presynaptic changes in GABAergic transmission. These results show that chronic DA depletion following 6-OHDA injection causes activity-dependent and -independent increase of synaptic GABAergic inhibition onto striatal NPY interneurons, confirming their involvement in the functional impairments of the DA-depleted striatum. Neuropeptide Y (NPY) interneurons regulate the function of striatal projection neurons and are upregulated upon dopamine depletion in the striatum. Here we investigated how dopamine depletion affects NPY circuits and show electrophysiologically that it leads to the occurrence of giant synaptic and burst GABAergic spontaneous inhibitory postsynaptic currents (IPSCs) and to an activity-independent increase in GABAergic miniature IPSC frequency in NPY neurons. We suggest that degeneration of dopaminergic terminals in the striatum causes functional changes in striatal GABAergic function.
作为基底神经节的主要输入核，纹状体在运动的计划、控制和执行以及运动技能学习中发挥着核心作用。超过90%的纹状体神经元，即所谓的中型多棘神经元（MSN），是γ-氨基丁酸（GABA）能投射神经元，主要支配黑质网状部或苍白球内侧部。其余的神经元是GABA能和胆碱能中间神经元，通过与MSN的相互连接来同步和控制纹状体输出。除了显著的局部胆碱能影响外，纹状体功能还受到来自黑质纹状体通路的多巴胺（DA）的全局调节。关于帕金森病中发生的DA耗竭是否会影响纹状体中间神经元的活动，目前知之甚少。在这里，我们聚焦于表达神经肽Y（NPY）的中间神经元，它们是纹状体中GABA能中间神经元的主要亚群之一。我们通过全细胞膜片钳技术，电生理记录6-羟基多巴胺（6-OHDA）注射组和对照组转基因NPY-人源化绿色荧光蛋白（hrGFP）小鼠脑片上已鉴定的NPY中间神经元的GABA能自发性（s）和微小（m）抑制性突触后电流（IPSC），研究纹状体DA耗竭对NPY中间神经元GABA能传递的影响。我们报告6-OHDA组的sIPSC和mIPSC频率显著增加，以及出现巨大突触性和爆发性sIPSCs，提示GABA能回路活动和突触传递发生了变化。IPSC动力学保持不变，表明GABA能传递主要发生了突触前变化。这些结果表明，6-OHDA注射后慢性DA耗竭导致对纹状体NPY中间神经元的突触GABA能抑制出现活动依赖性和非依赖性增加，证实它们参与了DA耗竭纹状体的功能损害。神经肽Y（NPY）中间神经元调节纹状体投射神经元的功能，并且在纹状体多巴胺耗竭时上调。在这里，我们研究了多巴胺耗竭如何影响NPY回路，并通过电生理学表明，它导致NPY神经元中出现巨大突触性和爆发性GABA能自发性抑制性突触后电流（IPSCs），以及GABA能微小IPSC频率出现非活动依赖性增加。我们认为，纹状体中多巴胺能终末的退化导致纹状体GABA能功能发生功能变化。
