Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden; Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden.
Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
Neurobiol Dis. 2018 Jan;109(Pt A):148-162. doi: 10.1016/j.nbd.2017.10.010. Epub 2017 Oct 14.
The intricate balance between dopaminergic and cholinergic neurotransmission in the striatum has been thoroughly difficult to characterize. It was initially described as a seesaw with a competing function of dopamine versus acetylcholine. Recent technical advances however, have brought this view into question suggesting that the two systems work rather in concert with the cholinergic interneurons (ChIs) driving dopamine release. In this study, we have utilized two transgenic Cre-driver rat lines, a choline acetyl transferase ChAT-Cre transgenic rat and a novel double-transgenic tyrosine hydroxylase TH-Cre/ChAT-Cre rat to further elucidate the role of striatal ChIs in normal motor function and in Parkinson's disease. Here we show that selective and reversible activation of ChIs using chemogenetic (DREADD) receptors increases locomotor function in intact rats and potentiate the therapeutic effect of L-DOPA in the rats with lesions of the nigral dopamine system. However, the potentiation of the L-DOPA effect is accompanied by an aggravation of L-DOPA induced dyskinesias (LIDs). These LIDs appear to be driven primarily through the indirect striato-pallidal pathway since the same effect can be induced by the D2 agonist Quinpirole. Taken together, the results highlight the intricate regulation of balance between the two output pathways from the striatum orchestrated by the ChIs.
纹状体中多巴胺能和胆碱能神经递质传递之间的复杂平衡一直难以描述。它最初被描述为一种跷跷板，多巴胺与乙酰胆碱的功能相互竞争。然而，最近的技术进步使这种观点受到质疑，表明这两个系统更像是协同工作，而胆碱能中间神经元（ChIs）驱动多巴胺释放。在这项研究中，我们利用了两种转基因 Cre 驱动大鼠系，一种是胆碱乙酰转移酶 ChAT-Cre 转基因大鼠和一种新型双重转基因酪氨酸羟化酶 TH-Cre/ChAT-Cre 大鼠，以进一步阐明纹状体 ChIs 在正常运动功能和帕金森病中的作用。在这里，我们表明使用化学遗传（DREADD）受体选择性和可逆地激活 ChIs 可增加完整大鼠的运动功能，并增强黑质多巴胺系统损伤大鼠中 L-DOPA 的治疗效果。然而，L-DOPA 效应的增强伴随着 L-DOPA 诱导的运动障碍（LIDs）的加重。这些 LIDs 似乎主要是通过间接纹状体苍白球通路驱动的，因为 D2 激动剂 Quinpirole 可以诱导相同的效果。总之，这些结果强调了纹状体中由 ChIs 协调的两个输出通路之间平衡的复杂调节。
