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 using 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.

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

“…Increased glutamate levels in the dorsal hippocampus persisted through late stage pathology so that GluCEST levels in PS19 mice exceeded those in WT mice by 13 months, agreeing with our previous report (Crescenzi et al, ). Increased glutamate levels observed in the PS19 hippocampus may be consistent with evidence of neuroprotective physiology, specifically hyperperfusion and hypermetabolism.…”

“…Contributions from other labile amine and amide protons contribute to <30% of the GluCEST asymmetry. Detailed descriptions of the GluCEST technique can be found in Cai et al (), Haris et al (), and Crescenzi et al ().…”

“…Previously GluCEST deficits have been measured in locations of severe synapse loss in a tauopathy mouse model (Crescenzi et al, ). However, this study focused on the late stage of disease after synapse loss and volume loss had already occurred.…”

Altered brain arginine metabolism in a mouse model of tauopathy

“…At 8 and 12–14 months of age, interestingly, there were reduced glutamate, but increased putrescine, levels in PS19 mice for all six regions (except for glutamate in the thalamus), indicating an age-related shift of channelling L-ornithine to produce putrescine. Crescenzi et al (2014) reported reduced glutamate levels in the CA (29%), but not the dentate gyrus, sub-regions of the hippocampus in 20-month PS19 mice using proton magnetic resonance spectroscopy. The present study found a 30% reduction in glutamate in the whole hippocampus of 12–14-month PS19 mice, which appears to be consistent with this earlier report.…”

Interrogating Metabolism in Brain Cancer

“…GluCEST imaging offers a resolution of 0.27 mm × 0.27 mm × 2 mm for animal model and 1.9 mm × 1.9 mm × 2 mm for human subjects with an imaging time of around 16s per slice (1 average), which is much better compared to conventional chemical shift imaging techniques in terms of spatial and temporal resolution. The total scan time is around 12 mins, including the acquisition of B0 and B1 maps needed for corrections (92, 93). …”