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Glutamate metabolism is altered in neurodegenerative disorders manifesting in higher or lower concentrations of glutamate, its transporters or receptors. Previously, glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) demonstrated that glutamate levels are reduced in regions of synapse loss in the hippocampus of a mouse model of late\u2010stage tauopathy. We performed a longitudinal GluCEST imaging experiment paired with a cross\u2010sectional study of histologic markers of tauopathy to determine whether (1) early GluCEST changes are associated with synapse loss before volume loss occurs in the hippocampus, and whether (2) subhippocampal dynamics in GluCEST are associated with histopathologic events related to glutamate alterations in tauopathy. Live imaging of the hippocampus in three serial slices was performed without exogenous contrast agents, and subregions were segmented based on a k\u2010means cluster model. Subregions of the hippocampus were analyzed (<jats:italic>cornu ammonis<\/jats:italic> CA1, CA3, dentate gyrus DG, and ventricle) in order to associate local MRI\u2010observable changes in glutamate with histological measures of glial cell proliferation (GFAP), synapse density (synaptophysin, VGlut1) and glutamate receptor (NMDA\u2013NR1) levels. Early differences in GluCEST between healthy and tauopathy mice were measured in the CA1 and DG subregions (30% reduction, <jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.001). Synapse density was also significantly reduced in every subregion of the hippocampus in tauopathy mice by 6\u00a0months. Volume was not significantly reduced in any subregion until 13\u00a0months. Further, a gradient in glutamate levels was observed <jats:italic>in vivo<\/jats:italic> along hippocampal axes that became polarized as tauopathy progressed. Dynamics in hippocampal glutamate levels throughout lifetime were most closely correlated with combined changes in synaptophysin and GFAP, indicating that GluCEST imaging may be a surrogate marker of glutamate concentration in glial cells and at the synaptic level. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/hipo.22693","type":"journal-article","created":{"date-parts":[[2016,12,20]],"date-time":"2016-12-20T23:02:49Z","timestamp":1482274969000},"page":"285-302","source":"Crossref","is-referenced-by-count":58,"title":["Longitudinal imaging reveals subhippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice"],"prefix":"10.1002","volume":"27","author":[{"given":"Rachelle","family":"Crescenzi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics (BMB) University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Center for Magnetic Resonance and Optical Imaging (CMROI) University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"DeBrosse","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics (BMB) University of Pennsylvania Philadelphia Pennsylvania"},{"name":"Center for Magnetic Resonance and Optical Imaging (CMROI) University of Pennsylvania Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi P. 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