title: Decreased purinergic inhibition of synaptic activity in a mouse model of Niemann-Pick disease type C.
abstract: Niemann-Pick disease type C (NPC) is a progressive neurodegenerative disorder characterized by accumulation of free cholesterol in lysosomes, mainly due to a mutation in the NPC1 gene. The pathophysiological basis of the neural disorders in NPC, however, is not well understood. We found that the hippocampal field excitatory postsynaptic potential (fEPSP) was enhanced in NPC1 mutant mice. A1-receptor antagonist or adenosine degrading enzyme enhanced the fEPSP in both types of mice, but had a much weaker effect in the mutant mice, suggesting less tonic inhibition of synaptic transmission by endogenous adenosine in the mutant. Further evidence showed impaired hippocampal long term potentiation (LTP) in mutant mice. Supplement of A1 agonist N6-Cyclopentyladenosine (CPA) partially rescued the impaired LTP in mutant mice. Moreover, adenosine release from hippocampal slices was significantly decreased in the mutant. The enhanced excitatory synaptic transmission and the decreased synaptic plasticity due to the decreased adenosine release in NPC brain may partially contribute to the neural disorders of NPC disease, such as seizures, neurodegeneration, and dementia.
authors.affiliation: Department of Neurobiology, Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Su-Ya
authors.initials: SY
authors.lastname: Zhou
authors.forename: Shu-Jun
authors.initials: SJ
authors.lastname: Xu
authors.forename: Ying-Gang
authors.initials: YG
authors.lastname: Yan
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Yu
authors.forename: Shu-Cai
authors.initials: SC
authors.lastname: Ling
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Luo
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000503:physiopathology; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D050505:Mutant Proteins / Q000235:genetics; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics; D043682:Receptor, Adenosine A1 / Q000502:physiology; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D043682:Receptor, Adenosine A1; D000241:Adenosine