4.7 Article

Differential modulation of subthalamic projection neurons by short-term and long-term electrical stimulation in physiological and parkinsonian conditions

期刊

ACTA PHARMACOLOGICA SINICA
卷 43, 期 8, 页码 1928-1939

出版社

NATURE PUBL GROUP
DOI: 10.1038/s41401-021-00811-4

关键词

subthalamic nucleus; electrical stimulation; substantia nigra pars reticulata; globus pallidus interna; synaptic inputs; firing; Parkinsonian mice

资金

  1. National Natural Science Foundation of China [81701100, 81870891, 81971038, 82071231, 82171235]
  2. Fund for Jiangsu Province Specially-Appointed Professor
  3. Natural Science Foundation of Jiangsu Province [BK20171160, BK20211349]
  4. Natural Science Foundation of the Jiangsu Higher Education Institutions of China [18KJA320009]
  5. Start Fund from Xuzhou Medical University [D2017009, D2017010]
  6. Postgraduate Innovation Program in Jiangsu Province [KYCX20_2474, KYCX20_2478]

向作者/读者索取更多资源

STN-SNr and STN-GPi neurons exhibit differences in synaptic inputs, responses to electrical stimulation, and modifications under parkinsonian conditions. These neurons may play crucial roles in the pathophysiology and therapeutic treatment of Parkinson's disease.
The subthalamic nucleus (STN) is one of the best targets for therapeutic deep brain stimulation (DBS) to control motor symptoms in Parkinson's disease. However, the precise circuitry underlying the effects of STN-DBS remains unclear. To understand how electrical stimulation affects STN projection neurons, we used a retrograde viral vector (AAV-retro-hSyn-eGFP) to label STN neurons projecting to the substantia nigra pars reticulata (SNr) (STN-SNr neurons) or the globus pallidus interna (GPi) (STN-GPi neurons) in mice, and performed whole-cell patch-clamp recordings from these projection neurons in ex vivo brain slices. We found that STN-SNr neurons exhibited stronger responses to depolarizing stimulation than STN-GPi neurons. In most STN-SNr and STN-GPi neurons, inhibitory synaptic inputs predominated over excitatory inputs and electrical stimulation at 20-130 Hz inhibited these neurons in the short term; its longer-term effects varied. 6-OHDA lesion of the nigrostriatal dopaminergic pathway significantly reduced inhibitory synaptic inputs in STN-GPi neurons, but did not change synaptic inputs in STN-SNr neurons; it enhanced short-term electrical-stimulation-induced inhibition in STN-SNr neurons but reversed the effect of short-term electrical stimulation on the firing rate in STN-GPi neurons from inhibitory to excitatory; in both STN-SNr and STN-GPi neurons, it increased the inhibition but attenuated the enhancement of firing rate induced by long-term electrical stimulation. Our results suggest that STN-SNr and STN-GPi neurons differ in their synaptic inputs, their responses to electrical stimulation, and their modification under parkinsonian conditions; STN-GPi neurons may play important roles in both the pathophysiology and therapeutic treatment of Parkinson's disease.

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