Decreased purinergic inhibition of synaptic activity in a mouse model of Niemann-Pick disease type C

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 hip...

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Bibliographic Details
Published in:Hippocampus 2011-02, Vol.21 (2), p.212-219
Main Authors: Zhou, Su-ya, Xu, Shu-jun, Yan, Ying-gang, Yu, Hui-mei, Ling, Shu-cai, Luo, Jian-hong
Format: Article
Language:English
Subjects:
adenosine
Adenosine - secretion
Animals
ATP
CA1 Region, Hippocampal - physiopathology
Disease Models, Animal
Electrophysiological Phenomena
excitability
Excitatory Postsynaptic Potentials
glutamatergic neuron
hippocampus
Hippocampus - physiopathology
Humans
In Vitro Techniques
Long-Term Potentiation
lysosome
Mice
Mice, Inbred BALB C
Mice, Mutant Strains
Mutant Proteins - genetics
neuronal excitotoxicity
Niemann-Pick Disease, Type C - genetics
Niemann-Pick Disease, Type C - physiopathology
Proteins - genetics
Receptor, Adenosine A1 - physiology
Synapses - physiology
Synaptic plasticity
Synaptic Transmission
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Summary: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. © 2010 Wiley‐Liss, Inc.
ISSN:1050-9631
1098-1063
DOI:10.1002/hipo.20741