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Ongoing clinical trials are attempting to reduce huntingtin (HTT) expression in the central nervous system (CNS) using different strategies. Yet, the distribution and timing of HTT\u2010lowering therapies required for a beneficial clinical effect is less clear. Here, we investigated whether HD\u2010related behaviours could be prevented by inactivating mutant HTT at different disease stages and to varying degrees in an experimental model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated mutant BACHD mice with either a widespread or circuit\u2010specific inactivation of mutant HTT by using Cre recombinase (Cre) under the nestin promoter or the adenosine A<jats:sub>2A<\/jats:sub> receptor promoter respectively. We also simulated a clinical gene therapy scenario with allele\u2010specific HTT targeting by injections of recombinant adeno\u2010associated viral (rAAV) vectors expressing Cre into the striatum of adult BACHD mice. All mice were assessed using behavioural tests to investigate motor, metabolic and psychiatric outcome measures at 4\u20136\u00a0months of age.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>While motor deficits, body weight changes, anxiety and depressive\u2010like behaviours are present in BACHD mice, early widespread CNS inactivation during development significantly improves rotarod performance, body weight changes and depressive\u2010like behaviour. However, conditional circuit\u2010wide mutant HTT deletion from the indirect striatal pathway during development and focal striatal\u2010specific deletion in adulthood failed to rescue any of the HD\u2010related behaviours.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results indicate that widespread targeting and the timing of interventions aimed at reducing mutant HTT are important factors to consider when developing disease\u2010modifying therapies for HD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12682","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T03:51:20Z","timestamp":1608263480000},"page":"564-578","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Effects of mutant huntingtin inactivation on Huntington disease\u2010related behaviours in the BACHD mouse 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