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Cerebellar 5HT-2A receptor mediates stress-induced onset of dystonia
Science Advances ( IF 13.6 ) Pub Date : 2021-03-03 , DOI: 10.1126/sciadv.abb5735
Jung Eun Kim 1 , Sujin Chae 2 , Sungsoo Kim 1 , Yeon-Joo Jung 3 , Myoung-Goo Kang 4 , Won Do Heo 1, 2 , Daesoo Kim 1, 2, 3
Affiliation  

Stress is a key risk factor for dystonia, a debilitating motor disorder characterized by cocontractions of muscles leading to abnormal body posture. While the serotonin (5HT) system is known to control emotional responses to stress, its role in dystonia remains unclear. Here, we reveal that 5HT neurons in the dorsal raphe nuclei (DRN) send projections to the fastigial deep cerebellar nuclei (fDCN) and that photostimulation of 5HT-fDCN induces dystonia in wild-type mice. Moreover, we report that photoinhibition of 5HT-fDCN reduces dystonia in a1Atot/tot mice, a genetic model of stress-induced dystonia, and administration of a 5HT-2A receptor inverse agonist (MDL100907; 0.1 to 1 mg/kg) or shRNA-mediated knockdown of the ht2ar gene in fDCN can notably reduce the onset of dystonia in a1Atot/tot mice. These results support the serotonin theory of dystonia and suggest strategies for alleviating symptoms in human patients by blocking 5HT-2A receptors.



中文翻译:

小脑 5HT-2A 受体介导应激诱导的肌张力障碍发作

压力是肌张力障碍的关键风险因素,肌张力障碍是一种使人衰弱的运动障碍,其特征是肌肉共同收缩导致身体姿势异常。虽然已知血清素 (5HT) 系统可以控制对压力的情绪反应,但其在肌张力障碍中的作用仍不清楚。在这里,我们揭示了中缝背核 (DRN) 中的 5HT 神经元向顶深小脑核 (fDCN) 发送投射,并且 5HT-fDCN 的光刺激诱导野生型小鼠肌张力障碍。此外,我们报告了 5HT-fDCN 的光抑制可减少 a1A tot/tot小鼠的肌张力障碍、应激诱导的肌张力障碍的遗传模型和 5HT-2A 受体反向激动剂(MDL100907;0.1 至 1 mg/kg)或 shRNA介导的fDCN 中ht2ar基因的敲低可以显着减少 a1A 肌张力障碍的发生tot/tot老鼠。这些结果支持肌张力障碍的血清素理论,并提出了通过阻断 5HT-2A 受体来缓解人类患者症状的策略。

更新日期:2021-03-04
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