In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy

Rachelle Crescenzi, Catherine DeBrosse, Ravi Prakash Reddy Nanga, Sanjana Reddy, Mohammad Haris, Hari Hariharan, Michiyo Iba, Virginia M Y Lee, John A. Detre, Arijitt Borthakur, Ravinder Reddy

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 (1H 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 1H 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.

Original languageEnglish
Pages (from-to)185-192
Number of pages8
JournalNeuroImage
Volume101
DOIs
Publication statusPublished - 1 Nov 2014
Externally publishedYes

Fingerprint

Tauopathies
Synapses
Glutamic Acid
Hippocampus
Brain
Pathology
Neurogenesis
Dentate Gyrus
Thalamus
Neurodegenerative Diseases
Transgenic Mice
Neurotransmitter Agents

Keywords

  • Chemical exchange saturation transfer
  • Dentate gyrus
  • Glutamate
  • Neurogenesis
  • Synapse loss
  • Tauopathy

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Neurology
  • Medicine(all)

Cite this

Crescenzi, R., DeBrosse, C., Nanga, R. P. R., Reddy, S., Haris, M., Hariharan, H., ... Reddy, R. (2014). In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy. NeuroImage, 101, 185-192. https://doi.org/10.1016/j.neuroimage.2014.06.067

In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy. / Crescenzi, Rachelle; DeBrosse, Catherine; Nanga, Ravi Prakash Reddy; Reddy, Sanjana; Haris, Mohammad; Hariharan, Hari; Iba, Michiyo; Lee, Virginia M Y; Detre, John A.; Borthakur, Arijitt; Reddy, Ravinder.

In: NeuroImage, Vol. 101, 01.11.2014, p. 185-192.

Research output: Contribution to journalArticle

Crescenzi, R, DeBrosse, C, Nanga, RPR, Reddy, S, Haris, M, Hariharan, H, Iba, M, Lee, VMY, Detre, JA, Borthakur, A & Reddy, R 2014, 'In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy', NeuroImage, vol. 101, pp. 185-192. https://doi.org/10.1016/j.neuroimage.2014.06.067
Crescenzi, Rachelle ; DeBrosse, Catherine ; Nanga, Ravi Prakash Reddy ; Reddy, Sanjana ; Haris, Mohammad ; Hariharan, Hari ; Iba, Michiyo ; Lee, Virginia M Y ; Detre, John A. ; Borthakur, Arijitt ; Reddy, Ravinder. / In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy. In: NeuroImage. 2014 ; Vol. 101. pp. 185-192.
@article{77991dcb84f748899b15b20b75d3e41e,
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 (1H 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 1H 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.",
keywords = "Chemical exchange saturation transfer, Dentate gyrus, Glutamate, Neurogenesis, Synapse loss, Tauopathy",
author = "Rachelle Crescenzi and Catherine DeBrosse and Nanga, {Ravi Prakash Reddy} and Sanjana Reddy and Mohammad Haris and Hari Hariharan and Michiyo Iba and Lee, {Virginia M Y} and Detre, {John A.} and Arijitt Borthakur and Ravinder Reddy",
year = "2014",
month = "11",
day = "1",
doi = "10.1016/j.neuroimage.2014.06.067",
language = "English",
volume = "101",
pages = "185--192",
journal = "NeuroImage",
issn = "1053-8119",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy

AU - Crescenzi, Rachelle

AU - DeBrosse, Catherine

AU - Nanga, Ravi Prakash Reddy

AU - Reddy, Sanjana

AU - Haris, Mohammad

AU - Hariharan, Hari

AU - Iba, Michiyo

AU - Lee, Virginia M Y

AU - Detre, John A.

AU - Borthakur, Arijitt

AU - Reddy, Ravinder

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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 (1H 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 1H 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.

AB - 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 (1H 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 1H 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.

KW - Chemical exchange saturation transfer

KW - Dentate gyrus

KW - Glutamate

KW - Neurogenesis

KW - Synapse loss

KW - Tauopathy

UR - http://www.scopus.com/inward/record.url?scp=84904858789&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904858789&partnerID=8YFLogxK

U2 - 10.1016/j.neuroimage.2014.06.067

DO - 10.1016/j.neuroimage.2014.06.067

M3 - Article

VL - 101

SP - 185

EP - 192

JO - NeuroImage

JF - NeuroImage

SN - 1053-8119

ER -