Huntington's disease knock-in male mice show specific anxiety-like behaviour and altered neuronal maturation

Huntington's disease (HD) is a devastating genetic neurodegenerative disorder. Major depressive disorder and more generally mood disorders are a major component of the symptoms during the pre-motor symptomatic stages of the disease. We report here that knock-in HdhQ111 mice, an animal model of HD, that carry an expanded polyglutamine stretch in the mouse HD protein show an anxio-depressive-like phenotype prior to any impairment of the locomotor function. Strikingly, whereas females develop preferentially a depressive-like behaviour, males had an increased anxiety-like phenotype. Since adult hippocampal neurogenesis has been associated to the pathophysiology and treatment of depression, we investigated whether changes in behavioural phenotypes are associated with proliferation or maturation impairments. Whereas cell proliferation was not affected in knock-in HdhQ111 mice, a male-specific marked decrease in late maturation of newborn neurons was observed in the adult dentate gyrus. Together, our results highlight sex differences in both behaviour and adult neurogenesis in a knock-in model of HD.

► HdhQ111 mice display an anxio-depressive-like behaviour without any motor impairment. ► HdhQ111 females are more depressive and HdhQ111 males are more anxious. ► HdhQ111 males present impaired hippocampal newborn neuron maturation.