Abstract
Huntington's disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD.
Highlights
Huntington’s disease (HD) is an inherited neurodegenerative disorder with symptomatic manifestations, including involuntary movements such as chorea, dystonia, poor motor coordination, psychiatric, and cognitive symptoms
Our findings reveal that the function of the M2 cortex-dorsolateral striatum (DLS) circuit is deeply impaired in the present HD mouse model, and indicate that selective stimulation of this pathway induces long-lasting plasticity effects that significantly ameliorate motor symptoms in HD
To evaluate distinct striatal circuit alterations in the transgenic R6/1 mouse model of HD, we studied the functional connectivity using resting-state fMRI in ~20-week-old R6/1 mice
Summary
Huntington’s disease (HD) is an inherited neurodegenerative disorder with symptomatic manifestations, including involuntary movements such as chorea, dystonia, poor motor coordination, psychiatric, and cognitive symptoms. HD is caused by a CAG repeat expansion in the huntingtin (Htt) gene that translates into a polyglutamine tract in the Htt protein. Mutant Htt (mHtt) is expressed throughout the brain and disrupts a wide range of molecular pathways and signaling cascades, yet HD pathology is most prominent in the basal ganglia circuitry. The central hub of the basal ganglia is the striatum, which controls movements and behavior through a myriad of inputs and outputs
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