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Cellular and Molecular Neurobiology

, Volume 39, Issue 2, pp 255–263 | Cite as

Molecular Imaging of mGluR5 Availability with [11C]ABP68 in Glutaminase Heterozygous Mice

  • Lauren Kosten
  • Steven Deleye
  • Sigrid Stroobants
  • Leonie Wyffels
  • Susana Mingote
  • Stephen Rayport
  • Steven StaelensEmail author
Original Research

Abstract

Many PET tracers enable determination of fluctuations in neurotransmitter release, yet glutamate specifically can not be visualized in a noninvasive manner. Several studies point to the possibility of visualizing fluctuations in glutamate release by changes in affinity of the mGluR5 radioligand [11C]ABP688. These studies use pharmacological challenges to alter glutamate levels, and so probe release, but have not measured chronic alterations in receptor occupancy due to altered neurotransmission relevant to chronic neuropsychiatric disorders or their treatment. In this regard, the GLS1 heterozygous mouse has known reductions in activity of the glutamate-synthetic enzyme glutaminase, brain glutamate levels and release. We imaged this model to elucidate glutamatergic systems. Dynamic [11C]ABP688 microPET scans were performed for mGluR5. Western blot was used as an ex vivo validation. No significant differences were found in BPND between WT and GLS1 Hets. SPM showed voxel-wise increased in BPND in GLS1 Hets compared to WT consistent with lower synaptic glutamate. This was not due to alterations in mGluR5 levels, as western blot results showed lower mGluR5 levels in GLS1 Hets. We conclude that because of the chronic glutaminase deficiency and subsequent decrease in glutamate, the mGluR5 protein levels are lowered. Due to these decreased endogenous glutamate levels, however, there is increased [11C]ABP688 binding to the allosteric site in selected regions. We speculate that lower endogenous glutamate leads to less conformational change to the receptors, and thus higher availability of the binding site. The lower mGluR5 levels, however, lessen [11C]ABP688 binding in GLS1 Hets, in part masking the increase in binding due to diminished endogenous glutamate levels as confirmed with voxel-wise analysis.

Keywords

Glutamate Micro PET Glutaminase Western blot mGluR5 

Abbreviations

[11C]ABP688

3-(6-Methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-[11C]-methyl-oxime

BPND

Nondisplaceable binding potential

CB

Cerebellum

CT

Computed tomography

FOV

Field of view

GLS1

Glutaminase

HIP

Hippocampus

Het

Heterozygous

i.v.

Intravenous

MID

Midbrain

mPFC

Medial prefrontal cortex

mGluR5

Metabotropic glutamate receptor 5

NMDA

N-methyl-d-aspartate

PAG

Phosphate-activated glutaminase

PET

Positron emission tomography

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SPM

Statistical parametric mapping

SRTM

Simplified reference tissue model

TAC

Time-activity curve

THA

Thalamus

VOI

Volume of interest

WT

Wild type

Notes

Acknowledgements

The collaboration with the Rayport laboratory at Columbia University was funded in part by FWO Grant V4.228.16N. We are grateful to Philippe Joye and Caroline Berghmans of MICA, University of Antwerp for their scan acquisitions, and to Christophe Deben and Annemie Van Eetveldt for their support setting up and executing the Western blot protocol.

Author Contributions

LK, StSt and SR contributed to conceptualization and manuscript revision; LK, SR, SM, StSt and SD involved in methodology; LW contributed to resources; LK and SD executed formal analysis; LK and StSt were involved in investigation; LK wrote original draft; StSt and SS contributed to supervision.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Molecular Imaging Center AntwerpUniversity of AntwerpAntwerpBelgium
  2. 2.Department of PsychiatryColumbia UniversityNew YorkUSA
  3. 3.Molecular TherapeuticsNYS Psychiatric InstituteNew YorkUSA
  4. 4.Department of Nuclear MedicineUniversity Hospital AntwerpAntwerpBelgium

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