Hyperactive Response of Direct Pathway Striatal Projection Neurons to L-dopa and D1 Agonism in Freely Moving Parkinsonian Mice.
Hyperactive Response of Direct Pathway Striatal Projection Neurons to L-dopa and D1 Agonism in Freely Moving Parkinsonian Mice.
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DOI：
10.3389/fncir.2018.00057
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发表时间：
2018
影响因子：
3.5
通讯作者：
Zhou FM
中科院分区：
文献类型：
--
作者：
Sagot B;Li L;Zhou FM
多巴胺（DA）深刻地刺激运动功能，如帕金森病（PD）中的运动功能减退症状和多巴胺能治疗PD期间的运动功能亢进副作用所证明的。多巴胺（DA）受体旁路，光遗传学和化学遗传学诱导的纹状体DA D1受体（D1 R）表达的尖峰放电，直接通路介质棘神经元（dSPN或dMSN）促进运动。然而，内源性D1 R介导的影响，更不用说DA替代，在自由移动的动物的dSPN穗活性没有建立。在这里，我们表明，使用转录因子Pitx 3无效突变体，（Pitx 3）小鼠作为帕金森病背侧纹状体中严重和一致的DA去神经支配的模型，逆行鉴定纹状体黑质神经元（D1 R表达的dSPN）具有比DA完整正常小鼠更低的基线尖峰放电率，这些神经元在Pitx 3小鼠中比在WT小鼠中更强烈地增加它们对注射L-多巴或D1 R激动剂SKF 81297的响应的棘波放电;尖峰放电的增加在时间上与L-多巴和SKF 81297的运动刺激作用一致。总之，这些结果提供了来自自由活动动物的第一个证据，即在帕金森病纹状体中，经鉴定的行为促进dSPN在给予L-多巴或D1激动剂后变得过度活跃，可能导致帕金森病动物和PD患者中的深刻多巴胺能运动刺激。
Dopamine (DA) profoundly stimulates motor function as demonstrated by the hypokinetic motor symptoms in Parkinson's disease (PD) and by the hyperkinetic motor side effects during dopaminergic treatment of PD. Dopamine (DA) receptor-bypassing, optogenetics- and chemogenetics-induced spike firing of striatal DA D1 receptor (D1R)-expressing, direct pathway medium spiny neurons (dSPNs or dMSNs) promotes movements. However, the endogenous D1R-mediated effects, let alone those of DA replacement, on dSPN spike activity in freely-moving animals is not established. Here we show that using transcription factor Pitx3 null mutant (Pitx3Null) mice as a model for severe and consistent DA denervation in the dorsal striatum in Parkinson's disease, antidromically identified striatonigral neurons (D1R-expressing dSPNs) had a lower baseline spike firing rate than that in DA-intact normal mice, and these neurons increased their spike firing more strongly in Pitx3Null mice than in WT mice in response to injection of L-dopa or the D1R agonist, SKF81297; the increase in spike firing temporally coincided with the motor-stimulating effects of L-dopa and SKF81297. Taken together, these results provide the first evidence from freely moving animals that in parkinsonian striatum, identified behavior-promoting dSPNs become hyperactive upon the administration of L-dopa or a D1 agonist, likely contributing to the profound dopaminergic motor stimulation in parkinsonian animals and PD patients.
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DOI：
10.1523/jneurosci.2192-08.2008
发表时间：
2008-10-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Berke JD
通讯作者：
Berke JD
影响因子：
5.5
作者：
Galati, Salvatore;Stanzione, Paolo;Stefani, Alessandro
通讯作者：
Stefani, Alessandro
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：
Ding, Shengyuan;Li, Li;Zhou, Fu-Ming
通讯作者：
Zhou, Fu-Ming
影响因子：
5.3
作者：
Ding, L;Perkel, DJ
通讯作者：
Perkel, DJ