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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.<\/jats:p>","DOI":"10.7554\/elife.57017","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T11:00:17Z","timestamp":1601895617000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.57017","source":"Crossref","is-referenced-by-count":42,"title":["M2 cortex-dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington\u2019s disease"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2281-4526","authenticated-orcid":true,"given":"Sara","family":"Fern\u00e1ndez-Garc\u00eda","sequence":"first","affiliation":[{"name":"Departament de Biomedicina, Institut de Neuroci\u00e8ncies, Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 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