Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice.
Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice.
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DOI：
10.1016/j.neuron.2015.12.038
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发表时间：
2016-02-17
期刊：
影响因子：
16.2
通讯作者：
Kreitzer AC
中科院分区：
文献类型：
--
作者：
Parker PR;Lalive AL;Kreitzer AC
帕金森病（PD）的运动抑制被认为是由于间接途径基底神经节回路相对于直接途径的功效增强而引起的。然而，潜在的病理生理机制仍然难以捉摸。为了研究这些回路的突触输入强度的变化是否有助于这种不平衡，我们获得了来自纹状体直接和间接通路中等多刺神经元（dMSN和iMSN）的配对全细胞记录，以及来自对照组和多巴胺耗尽小鼠脑切片中感觉运动皮层或板内丘脑的光学刺激输入。我们发现，多巴胺耗竭选择性地降低了丘脑输入dMSN的突触强度，这表明丘脑驱动基底神经节电路的不对称激活，这是帕金森氏症运动障碍的基础。与这一假设相一致，在体内化学和光遗传抑制丘脑纹状体终端逆转运动缺陷多巴胺耗尽的小鼠。这些结果暗示丘脑纹状体投射在PD的病理生理学中，并支持以丘脑为目标的干预措施作为潜在的治疗策略。
Movement suppression in Parkinson’s disease (PD) is thought to arise from increased efficacy of the indirect pathway basal ganglia circuit, relative to the direct pathway. However, the underlying pathophysiological mechanisms remain elusive. To examine whether changes in the strength of synaptic inputs to these circuits contribute to this imbalance, we obtained paired whole-cell recordings from striatal direct- and indirect-pathway medium spiny neurons (dMSNs and iMSNs) and optically stimulated inputs from sensorimotor cortex or intralaminar thalamus in brain slices from control and dopamine-depleted mice. We found that dopamine depletion selectively decreased synaptic strength at thalamic inputs to dMSNs, suggesting that thalamus drives asymmetric activation of basal ganglia circuitry underlying parkinsonian motor impairments. Consistent with this hypothesis, in vivo chemogenetic and optogenetic inhibition of thalamostriatal terminals reversed motor deficits in dopamine-depleted mice. These results implicate thalamostriatal projections in the pathophysiology of PD and support interventions targeting thalamus as a potential therapeutic strategy.