Formation of hippocampal mHTT aggregates leads to impaired spatial memory, hippocampal activation and adult neurogenesis.

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Serval ID
serval:BIB_E9315F777B6F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Formation of hippocampal mHTT aggregates leads to impaired spatial memory, hippocampal activation and adult neurogenesis.
Journal
Neurobiology of disease
Author(s)
Schwab L.C., Richetin K., Barker R.A., Déglon N.
ISSN
1095-953X (Electronic)
ISSN-L
0969-9961
Publication state
Published
Issued date
06/2017
Peer-reviewed
Oui
Volume
102
Pages
105-112
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by a triad of motor, psychiatric and cognitive deficits with the latter classically attributed to disruption of fronto-striatal circuits. However, emerging evidence suggests that some of the cognitive deficits in HD may have their origin in other structures including the hippocampus. Hippocampal abnormalities have been reported in HD mouse models particularly in terms of performance on the Morris Water Maze. However, in these animals, it is difficult to be certain whether the spatial memory deficits are due to local pathology within this structure or their poor mobility and motivation. Thus, a better model of hippocampal dysfunction in HD is needed especially given that we have previously shown that patients with HD have hippocampal-related problems from the very earliest stages of disease. In this study, our aim was therefore to understand the cellular and behavioural consequences of local overexpression of mutant huntingtin (mHTT) in the hippocampus of adult mice. We found that a targeted injection of a lentivirus, encoding an N-terminal of mHTT with 82 CAG repeats, into the murine hippocampus led to the focal formation of mHTT aggregates, long-term spatial memory impairments with decreased neurogenesis and expression of the immediate early gene c-fos. This study has therefore shown for the first time that local expression of mHTT in the dentate gyrus has deleterious effects, including its neurogenic capacity, with functional behavioural consequences, which fits well with recent data on hippocampal deficits seen in patients with HD.
Keywords
Animals, Disease Models, Animal, Female, Genetic Vectors, Hippocampus/metabolism, Hippocampus/pathology, Humans, Huntingtin Protein/administration & dosage, Huntingtin Protein/genetics, Huntingtin Protein/metabolism, Huntington Disease, Lentivirus, Maze Learning/physiology, Memory Disorders/etiology, Memory Disorders/metabolism, Memory Disorders/pathology, Mice, Inbred C57BL, Mutation, Neurogenesis/physiology, Neurons/metabolism, Neurons/pathology, Protein Aggregation, Pathological/complications, Protein Aggregation, Pathological/metabolism, Protein Aggregation, Pathological/pathology, Protein Aggregation, Pathological/psychology, Proto-Oncogene Proteins c-fos/metabolism, Spatial Memory/physiology, Adult neurogenesis, Dentate gyrus, Huntingtin, Lentiviral vectors, Memory, Neural progenitor cells
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Web of science
Create date
21/03/2017 19:25
Last modification date
19/06/2020 6:21
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