Optogenetic restoration of neuron subtype-specific cortical activity ameliorates motor deficits in Huntington’s Disease mice

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 dysfunctions, yet the role 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 two cortical inhibitory neuron (IN) subtypes and excitatory corticostriatal projection neurons (CSPNs) in the motor cortex of R6/2 HD mouse model throughout disease progression. We found that motor deficits in R6/2 mice were accompanied by neuron type-specific abnormalities in movement-related activity, including hypoactivity of vasoactive intestinal peptide (VIP)-INs and CSPNs. Optogenetic activation of VIP-INs in R6/2 mice restored healthy levels of activity in VIP-INs and their downstream CSPNs and ameliorated motor deficits in R6/2 mice. Our findings highlight cortical INs as a potential therapeutic target for HD and possibly other neurological diseases.