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

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

• Adult neurogenesis
• Memory
• Neural progenitor cells
• Dentate gyrus
• Huntingtin
• Lentiviral vectors