Striatal CDK5 Regulates Cholinergic Neuron Activation and Dyskinesia-like Behaviors through BK Channels  

作　　者：Chu Tong Peng-Xiang Min Qian Zhang Ru-Xin Gu Yao-Hai Wen Yi Shi Yu-Huan Bao Xiang Chen Yi-Xuan Zhang Xing-Feng Mao Hao-Yang Yuan Xiu-Xiu Liu Takuya Sasaki Li Zhang Feng Han Ying-Mei Lu 

机构地区：[1]Department of Physiology,School of Basic Medical Sciences,Nanjing Medical University,Nanjing,211166,China [2]International Joint Laboratory for Drug Target of Critical Illnesses,School of Pharmacy,Nanjing Medical University,Nanjing,211166,China [3]Department of Geriatrics,Nanjing Brain Hospital Affiliated to Nanjing Medical University,Nanjing,210029,China [4]Institute of Pharmacology and Toxicology,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China [5]Gusu School,Nanjing Medical University,Suzhou Municipal Hospital,The Affiliated Suzhou Hospital of Nanjing Medical University,Suzhou,215002,China [6]Department of Pharmacology,Graduate School of Pharmaceutical Sciences,Tohoku University,Sendai,980-8578,Japan [7]Institute of Brain Science,the Affiliated Brain Hospital of Nanjing Medical University,Nanjing,211166,China.

出　　处：《Research》2023年第4期739-753,共15页研究（英文）

基　　金：This work was supported by the National Key Research and Development Program of China(2022YFE0108600);the State Key Program of National Natural Science Foundations of China(81930103);the National Natural Science Foundations of China(81973300,82104162,and 82171249).

摘　　要：Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors.However,the molecular mechanisms underlying this disturbance remain elusive.Here,we showed that cyclin-dependent kinase 5(Cdk5)was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis.Serum levels of CDK5 also decreased in patients with Parkinson’s disease accompanied by motor symptoms.Moreover,Cdk5 deficiency in cholinergic neurons triggered paw tremors,abnormal motor coordination,and motor balance deficits in mice.These symptoms occurred along with cholinergic neuron hyperexcitability and increases in the current density of large-conductance Ca2+-activated K+channels(BK channels).Pharmacological inhibition of BK channels restrained the excessive intrinsic excitability of striatal cholinergic neurons in Cdk5-deficient mice.Furthermore,CDK5 interacted with BK channels and negatively regulated BK channel activity via phosphorylation of threonine-908.Restoration of CDK5 expression in striatal cholinergic neurons reduced dyskinesia-like behaviors in ChAT-Cre;Cdk5f/f mice.Together,these findings indicate that CDK5-induced phosphorylation of BK channels involves in cholinergic-neuronmediated motor function,providing a potential new therapeutic target for treating dyskinesia-like behaviors arising from neurological diseases.

关 键 词：CDK5 NEURON CDK5 

分 类 号：R741[医药卫生—神经病学与精神病学]