Aberrant Striatal Activity in Parkinsonism and Levodopa-Induced Dyskinesia.
Aberrant Striatal Activity in Parkinsonism and Levodopa-Induced Dyskinesia.
复制标题
DOI：
10.1016/j.celrep.2018.05.059
复制
发表时间：
2018-06-19
期刊：
影响因子：
8.8
通讯作者：
Nelson AB
中科院分区：
文献类型：
--
作者：
Ryan MB;Bair-Marshall C;Nelson AB
动作选择依赖于纹状体直接和间接通路中棘神经元（分别为dmsn和iMSNs）的协调活动。帕金森氏症患者多巴胺的缺失被认为会破坏这种平衡。虽然用左旋多巴替代多巴胺可以恢复正常功能，但不自主运动的发展（左旋多巴诱导的运动障碍，LID）限制了治疗。目前尚不清楚慢性多巴胺丢失和左旋多巴替代如何调节行为动物中已识别的msn的放电。利用光遗传学标记纹状体单单元记录，我们评估帕金森病和LID的电路功能障碍。与目前的模型相反，我们发现多巴胺耗竭后，iMSN放电仅在不活动期间升高，而dMSN放电则显著且持续减少。最值得注意的是，我们发现了一个dmsn亚群，其左旋多巴诱发的放电率异常高，这与运动障碍特别相关。这些发现为帕金森病和LID的电路机制提供了关键的见解，对开发新的靶向治疗方法具有重要意义。
Action selection relies on coordinated activity of striatal direct and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively). Loss of dopamine in Parkinson’s Disease is thought to disrupt this balance. While dopamine replacement with levodopa may restore normal function, the development of involuntary movements (levodopa-induced dyskinesia, LID) limits therapy. How chronic dopamine loss and replacement with levodopa modulate firing of identified MSNs in behaving animals is currently unknown. Using optogenetically labeled striatal single-unit recordings, we assess circuit dysfunction in parkinsonism and LID. Counter to current models, we found that following dopamine depletion, iMSN firing was elevated only during periods of immobility, while dMSN firing was dramatically and persistently reduced. Most notably, we identified a subpopulation of dMSNs with abnormally high levodopa-evoked firing rates, which correlated specifically with dyskinesia. These findings provide key insights into the circuit mechanisms underlying parkinsonism and LID, with implications for developing novel, targeted therapies.
登录
查看更多内容
影响因子：
64.8
作者：
Cui, Guohong;Jun, Sang Beom;Jin, Xin;Pham, Michael D.;Vogel, Steven S.;Lovinger, David M.;Costa, Rui M.
通讯作者：
Costa, Rui M.
影响因子：
2.5
作者：
BERGMAN, H;WICHMANN, T;DELONG, MR
通讯作者：
DELONG, MR
影响因子：
16.2
作者：
Gage, Gregory J.;Stoetzner, Colin R.;Wiltschko, Alexander B.;Berke, Joshua D.
通讯作者：
Berke, Joshua D.
DOI：
10.1073/pnas.1401819111
发表时间：
2014-03-25
影响因子：
11.1
作者：
Heiman, Myriam;Heilbut, Adrian;Greengard, Paul
通讯作者：
Greengard, Paul
影响因子：
11
作者：
HORSTINK, MWIM;ZIJLMANS, JCM;VANTHOF, MA
通讯作者：
VANTHOF, MA