Deficit in motor skill learning-dependent synaptic plasticity at motor cortex to Dorso Lateral Striatum synapses in a mouse model of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disease notably characterized by progressive motor symptoms. Although the loss of Medium Spiny Neurons (MSNs) in the striatum has been associated with motor deficits, 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 learning at the age of 11 to 14 weeks. Using optogenetic stimulation, we found that excitatory synaptic transmission from motor cortex to MSNs located in the Dorso Lateral part of the Striatum (DLS) is altered. Using single pellet reaching task, we observed that while motor skill learning is accompanied by a dynamic change in AMPA/NMDA ratio in wild type mice, this form of synaptic plasticity does not occur in YAC128 mice. This study not only proposes new meaningful insight the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill learning dependent synaptic plasticity at motor cortex to DLS synapses represents an early biomarker for Huntington's disease.