title: Defects of synaptic vesicle turnover at excitatory and inhibitory synapses in Niemann-Pick C1-deficient neurons.
abstract: Niemann-Pick disease type C (NPC) is a progressive neurodegenerative disorder characterized by accumulation of free cholesterol in late endosomes/lysosomes. The pathological basis for the disease is poorly understood. In the present study, electrophysiological and fluorescent dye studies were applied to examine neuron-specific functions of Niemann-Pick disease type C1 (NPC1) and to determine whether excitatory and inhibitory synapses are differentially impaired by NPC1 deficiency. Densities of spines and postsynaptic receptor clusters were not affected by NPC1 deficiency over the period examined. However, drastic defects on exocytosis were found both in glutamatergic and GABAergic synapses. The defects were caused in part by a delay in the time required for replacement of excytosed vesicles with new fusion-competent ones. Moreover, we found that the delay of synaptic vesicle turnover was longer in inhibitory synapses (>3 s) than in excitatory synapses (<0.2 s). These defects may be early indicators, and could provide a potential explanation for key features of the disease, such as dystonia and seizures.
authors.affiliation: Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Zhou
authors.forename: D
authors.initials: D
authors.lastname: Xia
authors.forename: J
authors.initials: J
authors.lastname: Xia
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Duan
authors.forename: J
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005089:Exocytosis / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D011930:Reaction Time / Q000502:physiology; D013569:Synapses / Q000378:metabolism; D013570:Synaptic Membranes / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*; D013572:Synaptic Vesicles / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid