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

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

Precision Radiotheranostics Translation Center (PRTC)

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English
Article number	899
Pages (from-to)	1-17
Number of pages	17
Journal	Brain Sciences
Volume	10
Issue number	12
DOIs	https://doi.org/10.3390/brainsci10120899
State	Published - Dec 2020

Keywords

3-[F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB)
Binding potential
Caudate nucleus
FMR1 gene
Fragile X Mental Retardation Protein (FMRP)
Genetic mutation
Magnetic resonance imaging (MRI)
Mosaicism
Neuropsychological testing
Positron emission tomography (PET)

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Brašić, J. R., Nandi, A., Russell, D. S., Jennings, D., Barret, O., Mathur, A., Slifer, K., Sedlak, T., Martin, S. D., Brinson, Z., Vyas, P., Seibyl, J. P., Berry-Kravis, E. M., Wong, D. F., & Budimirovic, D. B. (2020). Reduced expression of cerebral metabotropic glutamate receptor subtype 5 in men with fragile x syndrome. Brain Sciences, 10(12), 1-17. Article 899. https://doi.org/10.3390/brainsci10120899

@article{57bda7f37cf84fb3aecee7be41fa187e,

title = "Reduced expression of cerebral metabotropic glutamate receptor subtype 5 in men with fragile x syndrome",

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-[F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB), Binding potential, Caudate nucleus, FMR1 gene, Fragile X Mental Retardation Protein (FMRP), Genetic mutation, Magnetic resonance imaging (MRI), Mosaicism, Neuropsychological testing, Positron emission tomography (PET)",

author = "Bra{\v s}i{\'c}, {James R.} and Ayon Nandi and Russell, {David S.} and Danna Jennings and Olivier Barret and Anil Mathur and Keith Slifer and Thomas Sedlak and Martin, {Samuel D.} and Zabecca Brinson and Pankhuri Vyas and Seibyl, {John P.} and Berry-Kravis, {Elizabeth M.} and Wong, {Dean F.} and Budimirovic, {Dejan B.}",

note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = dec,

doi = "10.3390/brainsci10120899",

language = "English",

volume = "10",

pages = "1--17",

journal = "Brain Sciences",

issn = "2076-3425",

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Brašić, JR, Nandi, A, Russell, DS, Jennings, D, Barret, O, Mathur, A, Slifer, K, Sedlak, T, Martin, SD, Brinson, Z, Vyas, P, Seibyl, JP, Berry-Kravis, EM, Wong, DF & Budimirovic, DB 2020, 'Reduced expression of cerebral metabotropic glutamate receptor subtype 5 in men with fragile x syndrome', Brain Sciences, vol. 10, no. 12, 899, pp. 1-17. https://doi.org/10.3390/brainsci10120899

TY - JOUR

T1 - Reduced expression of cerebral metabotropic glutamate receptor subtype 5 in men with fragile x syndrome

AU - Brašić, James R.

AU - Nandi, Ayon

AU - Russell, David S.

AU - Jennings, Danna

AU - Barret, Olivier

AU - Mathur, Anil

AU - Slifer, Keith

AU - Sedlak, Thomas

AU - Martin, Samuel D.

AU - Brinson, Zabecca

AU - Vyas, Pankhuri

AU - Seibyl, John P.

AU - Berry-Kravis, Elizabeth M.

AU - Wong, Dean F.

AU - Budimirovic, Dejan B.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

KW - 3-[F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB)

KW - Binding potential

KW - Caudate nucleus

KW - FMR1 gene

KW - Fragile X Mental Retardation Protein (FMRP)

KW - Genetic mutation

KW - Magnetic resonance imaging (MRI)

KW - Mosaicism

KW - Neuropsychological testing

KW - Positron emission tomography (PET)

UR - http://www.scopus.com/inward/record.url?scp=85096707988&partnerID=8YFLogxK

U2 - 10.3390/brainsci10120899

DO - 10.3390/brainsci10120899

M3 - Article

C2 - 33255214

AN - SCOPUS:85096707988

SN - 2076-3425

VL - 10

SP - 1

EP - 17

JO - Brain Sciences

JF - Brain Sciences

IS - 12

M1 - 899

ER -

Reduced expression of cerebral metabotropic glutamate receptor subtype 5 in men with fragile x syndrome

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Keywords

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