Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome

James R Brašić; Ayon Nandi; David S Russell; Danna Jennings; Olivier Barret; Anil Mathur; Keith Slifer; Thomas Sedlak; Samuel D Martin; Zabecca Brinson; Pankhuri Vyas; John P Seibyl; Elizabeth M Berry-Kravis; Dean F Wong; Dejan B Budimirovic

doi:10.3390/brainsci10120899

Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome

Brain Sci. 2020 Nov 24;10(12):899. doi: 10.3390/brainsci10120899.

Authors

James R Brašić¹, Ayon Nandi¹, David S Russell^{2

3}, Danna Jennings^{2

3

4}, Olivier Barret², Anil Mathur¹, Keith Slifer^{5

6}, Thomas Sedlak^{1

7}, Samuel D Martin^{1

8}, Zabecca Brinson¹, Pankhuri Vyas¹, John P Seibyl^{2

3}, Elizabeth M Berry-Kravis⁹, Dean F Wong^{1

10}, Dejan B Budimirovic^{5

11}

Affiliations

¹ Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
² Clinical Research, Institute for Neurodegenerative Disorders, New Haven, CT 06510, USA.
³ Research Clinic, Invicro LLC, New Haven, CT 06510, USA.
⁴ Denali Therapeutics, Inc., South San Francisco, CA 94080, USA.
⁵ Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Behavioral Psychology, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
⁷ Department of Psychiatry and Behavioral Sciences-General Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Department of Neuroscience, Zanvyl Krieger School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA.
⁹ Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA.
¹⁰ Precision Radio-Theranostics Translational Laboratories, Mallinckrodt Institute of Radiology, School of Medicine, Washington University, Saint Louis, MO 63110, USA.
¹¹ Departments of Psychiatry and Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA.

Abstract

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR₅) in fmr1 knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR₅ expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR₅ density as a proxy of mGluR₅ expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluR₅s. The density and the distribution of mGluR₅ were measured in two independent samples of men with FXS (N = 9) and typical development (TD) (N = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR₅ expression showed that mGluR₅ expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.

Keywords: 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB); FMR1 gene; Fragile X Mental Retardation Protein (FMRP); binding potential; caudate nucleus; genetic mutation; magnetic resonance imaging (MRI); mosaicism; neuropsychological testing; positron emission tomography (PET).

Abstract

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