Parker Philip R L, Lalive Arnaud L, Kreitzer Anatol C
Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
Gladstone Institutes, San Francisco, CA 94158, USA.
Neuron. 2016 Feb 17;89(4):734-40. doi: 10.1016/j.neuron.2015.12.038. Epub 2016 Jan 28.
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.
帕金森病（PD）中的运动抑制被认为源于间接通路基底神经节回路相对于直接通路的效能增加。然而，潜在的病理生理机制仍然难以捉摸。为了研究这些回路突触输入强度的变化是否导致了这种失衡，我们从纹状体直接和间接通路中型多棘神经元（dMSN和iMSN）进行了配对全细胞记录，并在来自对照和多巴胺耗竭小鼠的脑片中对感觉运动皮层或板内核丘脑的输入进行了光学刺激。我们发现多巴胺耗竭选择性地降低了丘脑对dMSN输入的突触强度，表明丘脑驱动了帕金森病运动障碍背后基底神经节回路的不对称激活。与这一假设一致，体内化学遗传和光遗传抑制丘脑纹状体终末可逆转多巴胺耗竭小鼠的运动缺陷。这些结果表明丘脑纹状体投射参与了PD的病理生理过程，并支持将丘脑作为潜在治疗策略的干预措施。
