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mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treati...

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Autores principales: Stoppel, David C., McCamphill, Patrick K., Senter, Rebecca K., Heynen, Arnold J., Bear, Mark F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511445/
https://www.ncbi.nlm.nih.gov/pubmed/34658956
http://dx.doi.org/10.3389/fpsyt.2021.718953
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author Stoppel, David C.
McCamphill, Patrick K.
Senter, Rebecca K.
Heynen, Arnold J.
Bear, Mark F.
author_facet Stoppel, David C.
McCamphill, Patrick K.
Senter, Rebecca K.
Heynen, Arnold J.
Bear, Mark F.
author_sort Stoppel, David C.
collection PubMed
description Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.
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spelling pubmed-85114452021-10-14 mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence Stoppel, David C. McCamphill, Patrick K. Senter, Rebecca K. Heynen, Arnold J. Bear, Mark F. Front Psychiatry Psychiatry Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade. Frontiers Media S.A. 2021-09-29 /pmc/articles/PMC8511445/ /pubmed/34658956 http://dx.doi.org/10.3389/fpsyt.2021.718953 Text en Copyright © 2021 Stoppel, McCamphill, Senter, Heynen and Bear. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Psychiatry
Stoppel, David C.
McCamphill, Patrick K.
Senter, Rebecca K.
Heynen, Arnold J.
Bear, Mark F.
mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence
title mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence
title_full mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence
title_fullStr mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence
title_full_unstemmed mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence
title_short mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence
title_sort mglur5 negative modulators for fragile x: treatment resistance and persistence
topic Psychiatry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511445/
https://www.ncbi.nlm.nih.gov/pubmed/34658956
http://dx.doi.org/10.3389/fpsyt.2021.718953
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