Cortical efferents lacking mutant huntingtin improve striatal neuronal activity and behavior in a conditional mouse model of Huntington's disease.

Abnormal electrophysiological activity in the striatum, which receives dense innervation from the cerebral cortex, is believed to set the stage for the behavioral phenotype observed in Huntington's disease (HD), a neurodegenerative condition caused by mutation of the huntingtin (mhtt) protein. However, cortical involvement is far from clear. To determine whether abnormal striatal processing can be explained by mhtt alone (cell-autonomous model) or by mhtt in the corticostriatal projection cell-cell interaction model, we used BACHD/Emx1-Cre (BE) mice, a conditional HD model in which full-length mhtt is genetically reduced in cortical output neurons, including those that project to the striatum. Animals were assessed beginning at 20 weeks of age for at least the next 40 weeks, a range over which presymptomatic BACHD mice become symptomatic. Both open-field and nest-building behavior deteriorated progressively in BACHD mice relative to both BE and wild-type (WT) mice. Neuronal activity patterns in the dorsal striatum, which receives input from the primary motor cortex (M1), followed a similar age progression because BACHD activity changed more rapidly than either BE or WT mice. However, in the M1, BE neuronal activity differed significantly from both WT and BACHD. Although abnormal cortical activity in BE mice likely reflects input from mhtt-expressing afferents, including cortical interneurons, improvements in BE striatal activity and behavior suggest a critical role for mhtt in cortical output neurons in shaping the onset and progression of striatal dysfunction.

Dysregulated striatal neuronal processing and impaired motor behavior in mice lacking huntingtin interacting protein 14 (HIP14).

Palmitoyl acyl transferases (PATs) play a critical role in protein trafficking and function. Huntingtin interacting protein 14 (HIP14) is a PAT that acts on proteins associated with neuronal transmission, suggesting that deficient protein palmitoylation by HIP14, which occurs in the YAC128 model of Huntington's disease (HD), might have deleterious effects on neurobehavioral processing. HIP14 knockout mice show biochemical and neuropathological changes in the striatum, a forebrain region affected by HD that guides behavioral choice and motor flexibility. Thus, we evaluated the performance of these mice in two tests of motor ability: nest-building and plus maze turning behavior. Relative to wild-type controls, HIP14 knockout mice show impaired nest building and decreased turning in the plus maze. When we recorded the activity of striatal neurons during plus-maze performance, we found faster firing rates and dysregulated spike bursting in HIP14 knockouts compared to wild-type. There was also less correlated firing between simultaneously recorded neuronal pairs in the HIP14 knockouts. Overall, our results indicate that HIP14 is critically involved in behavioral modulation of striatal processing. In the absence of HIP14, striatal neurons become dysfunctional, leading to impaired motor behavior.