Longitudinal imaging reveals subhippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice

Tauopathies are neurodegenerative disorders characterized by abnormal intracellular aggregates of tau protein, and include Alzheimer's disease, corticobasal degeneration, frontotemporal dementia, and traumatic brain injury. 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‐stage tauopathy. We performed a longitudinal GluCEST imaging experiment paired with a cross‐sectional 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‐means cluster model. Subregions of the hippocampus were analyzed (cornu ammonis CA1, CA3, dentate gyrus DG, and ventricle) in order to associate local MRI‐observable changes in glutamate with histological measures of glial cell proliferation (GFAP), synapse density (synaptophysin, VGlut1) and glutamate receptor (NMDA–NR1) levels. Early differences in GluCEST between healthy and tauopathy mice were measured in the CA1 and DG subregions (30% reduction, P ≤ 0.001). Synapse density was also significantly reduced in every subregion of the hippocampus in tauopathy mice by 6 months. Volume was not significantly reduced in any subregion until 13 months. Further, a gradient in glutamate levels was observed in vivo 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. © 2016 Wiley Periodicals, Inc.

[1]  G. Juhász,et al.  Dysfunction of Endoplasmic Reticulum (ER) and Mitochondria (MT) in Alzheimer's Disease: The Role of the ER-MT Cross-Talk. , 2015, Current Alzheimer research.

[2]  Sébastien Ourselin,et al.  In vivo imaging of tau pathology using multi-parametric quantitative MRI , 2015, NeuroImage.

[3]  Paul M. Thompson,et al.  Effects of changing from non-accelerated to accelerated MRI for follow-up in brain atrophy measurement , 2015, NeuroImage.

[4]  G. Gerhardt,et al.  P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway , 2015, Journal of neurochemistry.

[5]  John A. Detre,et al.  In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy , 2014, NeuroImage.

[6]  E. Lein,et al.  Functional organization of the hippocampal longitudinal axis , 2014, Nature Reviews Neuroscience.

[7]  John L Robinson,et al.  Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old. , 2014, Brain : a journal of neurology.

[8]  M. Witter,et al.  Neuronal and Astrocytic Metabolism in a Transgenic Rat Model of Alzheimer's Disease , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  M. Stewart,et al.  Early Structural and Functional Defects in Synapses and Myelinated Axons in Stratum Lacunosum Moleculare in Two Preclinical Models for Tauopathy , 2014, PloS one.

[10]  Brian B. Avants,et al.  Histology-derived volumetric annotation of the human hippocampal subfields in postmortem MRI , 2014, NeuroImage.

[11]  M. Witter,et al.  Early Differences in Dorsal Hippocampal Metabolite Levels in Males But Not Females in a Transgenic Rat Model of Alzheimer’s Disease , 2013, Neurochemical Research.

[12]  E. Mandelkow,et al.  Regulatable transgenic mouse models of Alzheimer disease: onset, reversibility and spreading of Tau pathology , 2013, The FEBS journal.

[13]  L. Chin,et al.  Chronic traumatic encephalopathy – neuropathology in athletes and war veterans , 2013, Neurological research.

[14]  Ravinder Reddy,et al.  Imaging of glutamate neurotransmitter alterations in Alzheimer's disease , 2013, NMR in biomedicine.

[15]  R. Henson,et al.  Memory signals are temporally dissociated within and across human hippocampus and perirhinal cortex , 2012, Nature Neuroscience.

[16]  R. D'Hooge,et al.  Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau , 2012, Acta Neuropathologica.

[17]  J. Trojanowski,et al.  The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice , 2012, The Journal of Neuroscience.

[18]  John A. Detre,et al.  Magnetic Resonance Imaging of Glutamate , 2011, Nature Medicine.

[19]  Wolfgang Eberle,et al.  Synaptic dysfunction in hippocampus of transgenic mouse models of Alzheimer's disease: A multi-electrode array study , 2011, Neurobiology of Disease.

[20]  Janet S. Reddin,et al.  Voxel-level comparison of arterial spin-labeled perfusion MRI and FDG-PET in Alzheimer disease , 2011, Neurology.

[21]  B. Hyman,et al.  Neuropathological alterations in Alzheimer disease. , 2011, Cold Spring Harbor perspectives in medicine.

[22]  R. D'Hooge,et al.  Reversibility of Tau-Related Cognitive Defects in a Regulatable FTD Mouse Model , 2011, Journal of Molecular Neuroscience.

[23]  I. Grundke‐Iqbal,et al.  Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide , 2011, Neurobiology of Aging.

[24]  Cindee M. Madison,et al.  Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI , 2011, Neurobiology of Aging.

[25]  Stuart Maudsley,et al.  Amitriptyline-Mediated Cognitive Enhancement in Aged 3×Tg Alzheimer's Disease Mice Is Associated with Neurogenesis and Neurotrophic Activity , 2011, PloS one.

[26]  Jason S. Snyder,et al.  Septo-temporal gradients of neurogenesis and activity in 13-month-old rats , 2011, Neurobiology of Aging.

[27]  K. Ashe,et al.  Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration , 2010, Neuron.

[28]  G. Allan Johnson,et al.  Waxholm Space: An image-based reference for coordinating mouse brain research , 2010, NeuroImage.

[29]  Xavier Golay,et al.  High‐sensitivity cerebral perfusion mapping in mice by kbGRASE‐FAIR at 9.4 T , 2010, NMR in biomedicine.

[30]  J. Trojanowski,et al.  Epothilone D Improves Microtubule Density, Axonal Integrity, and Cognition in a Transgenic Mouse Model of Tauopathy , 2010, The Journal of Neuroscience.

[31]  John Q Trojanowski,et al.  A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. , 2010, The American journal of pathology.

[32]  C. Lippa,et al.  Review: Disruption of the Postsynaptic Density in Alzheimer’s Disease and Other Neurodegenerative Dementias , 2010, American journal of Alzheimer's disease and other dementias.

[33]  J. Trojanowski,et al.  Distinct cerebral perfusion patterns in FTLD and AD , 2010, Neurology.

[34]  H. Vinters,et al.  Synapse loss in dementias , 2010, Journal of neuroscience research.

[35]  J. Luebke,et al.  Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs , 2010, Experimental Neurology.

[36]  J. Raber,et al.  Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus , 2010, AGE.

[37]  Richard F. Thompson,et al.  Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease , 2010, Proceedings of the National Academy of Sciences.

[38]  Hong-wei Dong,et al.  Are the Dorsal and Ventral Hippocampus Functionally Distinct Structures? , 2010, Neuron.

[39]  M. Weiner,et al.  Relationships between biomarkers in aging and dementia , 2009, Neurology.

[40]  Arthur W. Toga,et al.  Genomic–anatomic evidence for distinct functional domains in hippocampal field CA1 , 2009, Proceedings of the National Academy of Sciences.

[41]  K. Kosik,et al.  Excitatory amino acid transporter 2 associates with phosphorylated tau and is localized in neurofibrillary tangles of tauopathic brains , 2009, FEBS letters.

[42]  A. McKee,et al.  Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy After Repetitive Head Injury , 2009, Journal of neuropathology and experimental neurology.

[43]  Jason S. Snyder,et al.  Anatomical gradients of adult neurogenesis and activity: Young neurons in the ventral dentate gyrus are activated by water maze training , 2009, Hippocampus.

[44]  James T Becker,et al.  Mild cognitive impairment and alzheimer disease: patterns of altered cerebral blood flow at MR imaging. , 2009, Radiology.

[45]  R. Wade-Martins,et al.  Knock-out and transgenic mouse models of tauopathies , 2009, Neurobiology of Aging.

[46]  Allan R. Jones,et al.  Genomic Anatomy of the Hippocampus , 2008, Neuron.

[47]  A. Delacourte,et al.  Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease , 2008, Neurobiology of Aging.

[48]  David C. Alsop,et al.  Hippocampal hyperperfusion in Alzheimer's disease , 2008, NeuroImage.

[49]  Clifford R. Jack,et al.  Antemortem MRI based STructural Abnormality iNDex (STAND)-scores correlate with postmortem Braak neurofibrillary tangle stage , 2008, NeuroImage.

[50]  T. Hafting,et al.  Finite Scale of Spatial Representation in the Hippocampus , 2008, Science.

[51]  H. Rusinek,et al.  Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer’s disease , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[52]  M. McKenna.  The glutamate‐glutamine cycle is not stoichiometric: Fates of glutamate in brain , 2007, Journal of neuroscience research.

[53]  D. Bennett,et al.  Paradoxical Upregulation of Glutamatergic Presynaptic Boutons during Mild Cognitive Impairment , 2007, The Journal of Neuroscience.

[54]  Bin Zhang,et al.  Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model , 2007, Neuron.

[55]  P Riederer,et al.  Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer's disease. , 2007, Journal of Alzheimer's disease : JAD.

[56]  M. Esiri,et al.  Down‐regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer's disease , 2006, Journal of neurochemistry.

[57]  R. Nitsch,et al.  Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic mice , 2006, Genes, brain, and behavior.

[58]  Ger J. A. Ramakers,et al.  Improved Long-Term Potentiation and Memory in Young Tau-P301L Transgenic Mice before Onset of Hyperphosphorylation and Tauopathy , 2006, The Journal of Neuroscience.

[59]  D. German,et al.  Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease , 2006, The Journal of comparative neurology.

[60]  M. Costanzi,et al.  NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[61]  Dietmar Schmitz,et al.  Synaptic plasticity at hippocampal mossy fibre synapses , 2005, Nature Reviews Neuroscience.

[62]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[63]  A. Ruifrok,et al.  Quantification of histochemical staining by color deconvolution. , 2001, Analytical and quantitative cytology and histology.

[64]  J. Trojanowski,et al.  Neurodegenerative tauopathies. , 2001, Annual review of neuroscience.

[65]  R. Fremeau,et al.  Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. , 2000, Science.

[66]  Leif Hertz,et al.  Astrocytes: Glutamate producers for neurons , 1999, Journal of neuroscience research.

[67]  A. Wree,et al.  Septotemporal distribution of [3H]MK-801, [3H]AMPA and [3H]Kainate binding sites in the rat hippocampus , 1998, Anatomy and Embryology.

[68]  S. Budd,et al.  Mitochondria and neuronal glutamate excitotoxicity. , 1998, Biochimica et biophysica acta.

[69]  F. Fonnum,et al.  Uptake of glutamate into synaptic vesicles. , 1998, Progress in brain research.

[70]  J. Morrison,et al.  Non-plaque dystrophic dendrites in Alzheimer hippocampus: a new pathological structure revealed by glutamate receptor immunocytochemistry , 1997, Neuroscience.

[71]  A. Delacourte,et al.  Glial reaction in the hippocampal formation is highly correlated with aging in human brain , 1997, Neuroscience Letters.

[72]  L. Swanson,et al.  Structural Evidence for Functional Domains in the Rat Hippocampus , 1996, Science.

[73]  R. Rubin,et al.  Reduction of AMPA-selective glutamate receptor subunits in the entorhinal cortex of patients with Alzheimer's disease pathology: a biochemical study , 1995, Brain Research.

[74]  C. Finch,et al.  Increases of glial fibrillary acidic protein in the aging female mouse brain , 1995, Neurobiology of Aging.

[75]  A. Schousboe,et al.  Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited. , 1995, Developmental neuroscience.

[76]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[77]  D. Graham,et al.  Glutamate metabotropic and AMPA binding sites are reduced in Alzheimer's disease: an autoradiographic study of the hippocampus , 1991, Brain Research.

[78]  R. Faull,et al.  Alzheimer's disease: Changes in hippocampal N-methyl-d-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors—an autoradiographic study , 1990, Neuroscience.

[79]  S. DeKosky,et al.  Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity , 1990, Annals of neurology.

[80]  J. Penney,et al.  Excitatory amino acid binding sites in the hippocampal region of Alzheimer's disease and other dementias. , 1990, Journal of neurology, neurosurgery, and psychiatry.

[81]  A. Young,et al.  Excitatory amino acids and Alzheimer's disease , 1989, Neurobiology of Aging.

[82]  T. Teyler.  Long-term potentiation and memory. , 1987, International journal of neurology.

[83]  T. Bliss,et al.  Long-term potentiation of the perforant path in vivo is associated with increased glutamate release , 1982, Nature.

[84]  Arne Schousboe,et al.  Transport and Metabolism of Glutamate and Gaba in Neurons and Glial Cells , 1981 .

[85]  A. M. Benjamin,et al.  METABOLISM OF AMINO ACIDS AND AMMONIA IN RAT BRAIN CORTEX SLICES IN VITRO: A POSSIBLE ROLE OF AMMONIA IN BRAIN FUNCTION , 1975, Journal of neurochemistry.

[86]  H. Weissbach,et al.  Metabolism of amino acids. , 1960, Annual review of biochemistry.