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

Abstract

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 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 Dorso Lateral part of the Striatum (DLS) is altered. Using single pellet reaching task, we observed that while motor skill consolidation 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 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 Huntington’s disease.

Significance Statement Huntington’s disease (HD) is a neurodegenerative disease characterized by prominent motor manifestations in addition to nonmotor changes in behavior and cognition. Several studies have provided evidences that the neuropathological hallmark of HD begins and progresses before the conventional diagnosis can be made. Here using an animal model, we identified deficit in motor skill in early stage of the disease. Remarkably these early behavioural deficits are accompanied by aberrant plasticity at synapses between motor cortex and dorsal striatum. This study not only gives a better understanding in the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill consolidation-dependent synaptic plasticity at motor cortex to dorsal striatum synapses represents an early biomarker for Huntington’s disease.