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Dysfunction of synaptic endocytic trafficking in Parkinson's disease

Neural Regeneration Research 2024年第12期19卷 2649-2660页

作者： Xin Yi Ng Mian Cao Programme in Neuroscience and Behavioural Disorders Duke-NUS Medical SchoolSingaporeSingapore Department of Physiology National University of SingaporeSingaporeSingapore

Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum.The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive.Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease.Notably,several of these genes are linked to the synaptic vesicle recycling process,particularly the clathrinmediated endocytosis pathway.This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease,followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a"dying back"mechanism.Recently,several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized.These models faithfully recapitulate certain Parkinson's disease-like features at the animal,circuit,and cellular levels,and exhibit defects in synaptic membrane trafficking,further supporting the findings from human genetics and clinical studies.In this review,we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins:auxilin(DNAJC6/PARK19)and synaptojanin 1(SYNJ1/PARK20).The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect.Subsequently,we will delve into the involvement of several clathrin-mediated endocytosis-related proteins(GAK,endophilin A1,SAC2/INPP5 F,synaptotagmin-11),identified as Parkinson's disease risk factors through genome-wide association studies,in Parkinson's disease pathogenesis.We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins(alpha-synuclein(PARK1/4),Parkin(PARK2),and LRRK2(PARK8))in synaptic endocytic trafficking.Additionall

关键词： autophagy auxilin/PARK19 clathrin-mediated endocytosis dopamine neurons neurodegeneration nigrostriatal pathway Parkinson's disease synaptic vesicle recycling synaptojanin1/PARK20

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Chemogenetic stimulation of nigrostriatal and mesolimbic projections affects sleep-wake behavior in rat

Chemogenetic stimulation of nigrostriatal and mesolimbic pro...

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中国神经科学学会第十二届全国学术会议

作者： Mei-Hong Qiu Michael C.Chen Jun Lu Department of Neurobiology School of Basic Medical Science Fudan University Department of Neurology Beth Israel Deaconess Medical Center and Harvard Medical School Department of Pharmacology School of Basic Medical Science Fudan University

Dopamine plays a complex role in sleep-wake systems. The exact effect of dopamine on these behaviors may depend on the downstream target of dopamine pathways. Using selective chemogenetic stimulation in rats, we dissected midbrain dopaminergic nigrostriatal and mesolimbic pathways and their effects on sleep. Chemogenetic stimulation of nigrostriatal pathways increased sleep and cortical EEG delta power, while chemogenetic stimulation of mesolimbic pathways decreased sleep and cortical EEG power. These results indicate that midbrain dopamine（DA） in the basal ganglia has distinct roles in sleep-wake regulation.

关键词： dopamine sleep-wake mesolimbic pathway nigrostriatal pathway chemogenetic

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Influence of the MFB stimulation on the mesencephalic dopaminergic system

Influence of the MFB stimulation on the mesencephalic dopami...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Qian LI~(1,2),Shao-Min ZHANG~(1,2,*),Yi YU~(1,2),Huai-Jian ZHANG~(1,2),Qiao-Sheng ZHANG~(1,2),Xiao-Xiang ZHENG~(1,2) 1 Qiushi Academy for Advanced Studies,Zhejiang University,Hangzhou 310027,China 2 College of Biomedical Engineering and Instrument Science,Zhejiang University,Hangzhou 310027,China

＜正＞Objective As the main component of brain’s reward center,the electrical stimulation of the medial forebrain bundle（MFB） leads to the activation of the mesocorticolimbic dopaminergic pathway.Such effect elicits the intense intracranial self-stimulation（ICSS）,which strengthens the rats to perform a series of reward-motivated reinforcement behavior.As the MFB is assembled by the axon bundles of dopaminergic neurons both in the mesocorticolimbic pathway and nigrostriatal pathway,the present study aims to explore that the MFB stimulation not only activates the brain’s reward center,but also impacts the nigrostriatal pathway,which participates the cortico-basal ganglia loop.Methods 18 adult male Sprague-Dawley rats were randomly divided into GroupsⅠ,ⅡandⅢ.Group I:stimulating electrode was implanted into hibateral MFB（Aβ:-3.60;ML:±1.80;DV:+9.20）.By using an eight-arm radial maze,the rat’s preferable turning direction was recorded when the stimulation was delivered in the arm exit,which reliably reflected the different effects of MFB stimulation on the locomotor behavior of bilateral limbs.Group II:stimulating electrode and single-channel local field potential（LFP） recording electrode were implanted into the bilateral MFB and the primary cerebral cortex（M1, Aβ:+2.50;ML:±3.00;DV:+1.20）.After recording the Ml-LFPs pre and post stimulation,wavelet packet transform（WPT） was applied to make time-frequency spectrum analysis.GroupⅢ:stimulating electrode and 7-channel spike recording bundle were implanted into the unilateral MFB and the ipsilateral entopeduncular nucleus（EP,Aβ:-2.40;ML:±2.80;DV: +7.60）.After getting the EP-spikes pre and post stimulation,detecting and sorting algorithm helped to draw each neuron’s raster.Peri-Stimulus Time Histogram（PSTH） and Inter-Spike Intervals（ISIs） were plotted to decode the firing patterns of the EP-GABAergic neurons.Results（1）Unilateral MFB stimulation caused a striking asymmetry in the rat’s locomotor behavior.The contralateral turning was predominate in numbers（P＜0.001）.（2） 100-400 m

关键词： medical forebrain bundle mesocorticolimbic dopaminergic pathway nigrostriatal pathway basal ganglia extrapyramidal system

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