Promoting cortical disinhibition ameliorates Huntington's disease phenotypes

Huntington’s disease (HD) is a devastating movement disorder without a current cure . Although the monogenic basis of HD is well-defined , the complex downstream effects that underlie behavioral symptoms are poorly understood. These effects include cortical dysfunction, yet the roles of specific cortical neuronal subtypes in HD symptoms remain largely unexplored. Here, we used longitudinal in vivo two-photon calcium imaging to examine the activity of three cortical inhibitory neuron (IN) subtypes and excitatory corticostriatal (CStr) projection neurons in the motor cortex of the transgenic R6/2 HD mouse model throughout disease progression. We found that motor deficits in R6/2 mice were accompanied by neuron subtype-specific abnormalities in movement-related activity. This included marked hypoactivity of vasoactive intestinal peptide (VIP)-INs and CStr neurons, which was also observed in the knock-in zQ175DN HD mouse model. Optogenetic activation of VIP-INs in R6/2 mice restored healthy levels of activity in VIP-INs and their downstream CStr neurons and ameliorated motor deficits in R6/2 mice. Remarkably, behavioral improvements persisted for days after stimulation. Our findings highlight cortical INs as a potential therapeutic target for HD.