Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of StriatalCholinergic Interneurons (Neuron,2016,91(1):67-78)

報告日期: 2016/11/18
報告時間: 5:10/6:00
報告學生: 楊正毅
講評老師: 郭余民
附件下載: 下載[1577-1473666470-1.pdf] 

Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons

Geetika Kharkwal,Karen Brami-Cherrier,Jose´ E. Lizardi-Ortiz,Alexandra B. Nelson,Maria Ramos,

Daniel Del Barrio, David Sulzer, Anatol C. Kreitzer,and Emiliana Borrelli

Neuron 91(1): 67-78, 2016

Speaker: 楊正毅                                                              Date: 11/18/2016

Commentator: 郭余民老師                                                 Place: Room 602

 

    Striatal circuits are important for motor, cognitive and emotional function. Inside the striatum, medium spiny neurons (MSNs) are the most abundant neurons with only a few cholinergic interneurons (ChIs). MSNs and ChIs are regulated by dopamine and acetylcholine and thus making a fine balance in striatal function. When dopamine dysregulation happens, patients suffer from psychotics like schizophrenia. Typical antipsychotics are designed to antagonize D2 receptors. However, typical antipsychotics like haloperidol can induce extrapyramidal symptoms (EPS) in human, catalepsy in rodents. Because MSNs and ChIs are both regulated by D2R, the authors sought to figure out the mechanisms underlying this side effects through cholinergic interneurons despite its low number in striatum. Using ChI-specific D2RKO mice, ChI-D2RKO mice showed less response to D2R agonist and different response to intrastriatal pulse. Surprisingly, giving D2R antagonist haloperidol, ChI-DRKO mice showed no catalepsy while significant catalepsy could be observed in WT dose-dependently. Consistently, both ChIs and D2R+-MSNs were not activated after treating haloperidol in ChI-D2RKO mice. Without D2R, acetylcholine release regulation from dopamine were lost, which consequently lead to reduction in cholinergic signaling due to autoreceptor-mediated self-inhibition. After giving combined treatment with haloperidol and donepezil, ChI-D2RKO mice exhibited catalepsy. Together, these results indicated that typical antipsychotics-induced side effects are related to cholinergic interneurons-mediated cholinergic signaling in striatum and are regulated by dopamine.

 

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