title: In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy.
abstract: Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and several other tauopathies. The current method for measuring glutamate in vivo is proton magnetic resonance spectroscopy ((1)H MRS), although it has poor spatial resolution and weak sensitivity to glutamate changes. In this study, we sought to measure the effect of tau pathology on glutamate levels throughout the brain of a mouse model of tauopathy using a novel magnetic resonance imaging (MRI) technique. We employed glutamate chemical exchange saturation transfer (GluCEST) imaging, which has been previously validated as a complimentary method for measuring glutamate levels with several important advantages over conventional (1)H MRS. We hypothesized that the regional changes in glutamate levels would correlate with histological measurements of pathology including pathological tau, synapse and neuron loss. Imaging and spectroscopy were carried out on tau transgenic mice with the P301S mutation (PS19, n=9) and their wild-type littermates (WT, n=8), followed by immunohistochemistry of their brain tissue. GluCEST imaging resolution allowed for sub-hippocampal analysis of glutamate. Glutamate was significantly decreased by 29% in the CA sub-region of the PS19 hippocampus, and by 15% in the thalamus, where synapse loss was also measured. Glutamate levels and synapse density remained high in the dentate gyrus sub-region of the hippocampus, where neurogenesis is known to occur. The further development of GluCEST imaging for preclinical applications will be valuable, as therapies are being tested in mouse models of tauopathy.
authors.affiliation: Department of Biochemistry and Molecular Biophysics (BMB), University of Pennsylvania, Philadelphia, PA, USA; Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: bergerra@mail.med.upenn.edu.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Crescenzi
authors.affiliation: Department of Biochemistry and Molecular Biophysics (BMB), University of Pennsylvania, Philadelphia, PA, USA; Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: DeBrosse
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ravi Prakash Reddy
authors.initials: RP
authors.lastname: Nanga
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sanjana
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Haris
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Hari
authors.initials: H
authors.lastname: Hariharan
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), Department of Pathology & Lab Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Iba
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), Department of Pathology & Lab Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Center for Functional Neuroimaging (CFN), Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Detre
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Arijitt
authors.initials: A
authors.lastname: Borthakur
authors.affiliation: Center for Magnetic Resonance and Optical Imaging (CMROI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Reddy
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology; D066244:Proton Magnetic Resonance Spectroscopy; D013569:Synapses / Q000473:pathology*; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology; D013788:Thalamus / Q000378:metabolism* / Q000473:pathology
chemical_list: D018698:Glutamic Acid
keywords: Chemical exchange saturation transfer; Dentate gyrus; Glutamate; Neurogenesis; Synapse loss; Tauopathy