Progression of behavioural despair in R6/2 and Hdh knock-in mouse models recapitulates depression in Huntington's disease

•We studied forced swim test behaviours in R6/2 and Hdh knock-in mice.•In both lines, increased despair (floating) was shown at an early stage of disease progression.•In both lines, early-stage floating levels decreased as the mice aged.•Increased swimming and climbing behaviours were observed in late-stage HD mice.

In Huntington's disease (HD) depression is observed before the disease is diagnosed, and is likely to be a component of the disease, rather than a consequence. Depression in HD patients does not progress in parallel with other symptoms; rather it peaks at early- to mid-stages of the disease and declines thereafter. In mice, depressive-like behaviours can be measured as an increase in behavioural despair (floating) observed in the forced swim test (FST). Floating in the FST is modulated differently by antidepressants with different mechanisms of action. Drugs that increase levels of serotonin inhibit floating by promoting horizontal swimming, whereas drugs that increase levels of noradrenaline inhibit floating by enhancing vertical swimming (climbing). We compared the FST behavioural profiles of two different allelic series of HD mice, a fragment model (R6/2 mice carrying 120, 250, or 350 CAG repeats), and a knock-in model (Hdh mice carrying 50, 150, or 250 CAG repeats). The FST behavioural profile was similar in both lines. It was characterized by an early-stage increase in floating, and then, as the mice aged, floating decreased, whereas active behaviours of swimming and climbing increased. Our results show that, as with depression in HD patients, floating in HD mice does not progress linearly, suggesting that, at the late stages of the disease, an increase in serotonergic and noradrenergic activity might contribute to lower floating levels in HD mice. If similar compensatory changes occur in humans, this should be taken into account when considering the treatment of depression in HD patients.