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mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence

Authors :
Mark F. Bear
Rebecca K Senter
Arnold J. Heynen
David C. Stoppel
Patrick K. McCamphill
Source :
Frontiers in Psychiatry, Frontiers in Psychiatry, Vol 12 (2021)
Publication Year :
2021
Publisher :
Frontiers Media SA, 2021.

Abstract

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.

Details

ISSN :
16640640
Volume :
12
Database :
OpenAIRE
Journal :
Frontiers in Psychiatry
Accession number :
edsair.doi.dedup.....1cabe950f76a8dbaa7e70008b20d765f
Full Text :
https://doi.org/10.3389/fpsyt.2021.718953