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We conducted in vivo longitudinal <jats:sup>1<\/jats:sup>H\u2010MRS in the striatum followed by ex vivo analyses of excitatory synapse density of two synaptic circuits disrupted in HD, thalamo\u2010striatal (T\u2010S), and cortico\u2010striatal (C\u2010S) pathways, to assess the relationship between neurochemical alterations and changes in synapse density. We used the zQ175<jats:sup>(Tg\/0)<\/jats:sup> HD mouse model as well as zQ175 mice lacking one allele of CK2\u03b1\u2019(zQ175<jats:sup>(Tg\/0)<\/jats:sup>:CK2\u03b1\u2019<jats:sup>(+\/\u2212)<\/jats:sup>), a kinase previously shown to regulate synapse function in HD. Longitudinal analyses of excitatory synapse density showed early and sustained reduction in T\u2010S synapses in zQ175 mice, preceding C\u2010S synapse depletion, which was rescued in zQ175:CK2\u03b1\u2019<jats:sup>(+\/\u2212)<\/jats:sup>. Changes in T\u2010S and C\u2010S synapses were accompanied by progressive alterations in numerous neurochemicals between WT and HD mice. Linear regression analyses showed C\u2010S synapse number positively correlated with <jats:sup>1<\/jats:sup>H\u2010MRS\u2010measured levels of GABA, while T\u2010S synapse number positively correlated with levels of phosphoethanolamine and negatively correlated with total creatine levels. These associations suggest that these neurochemical concentrations measured by <jats:sup>1<\/jats:sup>H\u2010MRS may facilitate monitoring circuit\u2010specific synaptic dysfunction in the zQ175 mouse model and in other HD pre\u2010clinical studies.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15714-fig-0005-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15714","type":"journal-article","created":{"date-parts":[[2022,10,22]],"date-time":"2022-10-22T15:29:35Z","timestamp":1666452575000},"page":"226-241","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Neurochemical correlates of synapse density in a Huntington's disease mouse 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