Deficit in Motor Skill Consolidation-Dependent Synaptic Plasticity at Motor Cortex to Dorsolateral Striatum Synapses in a Mouse Model of Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disease notably characterized by progressive motor symp-toms. Although the loss of medium spiny neurons (MSNs) in the striatum has been associated with motor defi-cits, premanifest patients already present cognitive deficiencies and show early signs of motor disabilities. Here, in a YAC128 HD mouse model, we identified impairment in motor skill consolidation at the age of 11- 14 weeks. Using optogenetic stimulation, we found that excitatory synaptic transmission from motor cortex to MSNs located in the dorsolateral part of the striatum (DLS) is altered. Using single pellet reaching task, we ob-served that while motor skill consolidation is accompanied by a dynamic change in AMPA/NMDA ratio in wild -type (WT) mice, this form of synaptic plasticity does not occur in YAC128 mice. This study not only proposes new meaningful insight in the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill consolidation-dependent synaptic plasticity at motor cortex to DLS synapses represents an early biomarker for HD.