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Purpose of review <p>This review summarizes the current evidence regarding the role of metabotropic glutamate receptor 5 (mGluR5) in autism spectrum disorder (ASD) integrating genetic, molecular, neuroimaging, and therapeutic evidence to evaluate the mGluR5 related pathways in ASD mechanisms and evaluate its potential as a therapeutic target.</p> Recent findings <p>Genetic studies report 25-fold peripheral GRM5 downregulation in ASD patients, with specific variants (rs905646, rs762724) showing biased paternal transmission and associations with increased symptom severity. Advances in super resolution imaging demonstrate that mGluR5 is confined to perisynaptic nanodomains with restricted lateral mobility, forming localized signaling microdomains critical for synaptic modulation. First in-human positron emission tomography (PET) studies using [<sup>18</sup>F]3-Fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([<sup>18</sup>F]-FPEB) reveal region specific alterations in mGluR5 availability in ASD, including increased binding in the striatum and thalamus, which correlates inversely with cortical GABA concentrations. In preclinical models, both positive and negative allosteric modulation of mGluR5 has been shown to improve social and repetitive behavioral phenotypes, although these effects are highly contextual and model dependent.</p> Summary <p>Collectively, available evidence suggests that dysregulation of mGluR5-associated signaling represents a convergent molecular mechanism in biologically defined subsets of ASD, rather than a universal pathogenic feature. Alterations in synaptic scaffolding complexes (SHANK3–Homer–mGluR5 interactions), receptor trafficking, and activity-dependent protein synthesis may contribute to excitatory/inhibitory imbalance and circuit dysfunction. While preclinical findings support mGluR5 as a therapeutic target, mixed results from clinical trials underscore significant translational challenges. Future therapeutic strategies will require genetically and biologically stratified cohorts, robust pharmacodynamic biomarkers, and multimodal approaches integrating peripheral molecular measures with advanced neuroimaging to refine mGluR5-targeted interventions.</p> Graphical abstract <p></p>

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Unraveling mGluR5 dysfunction in autism spectrum disorder: a multi-level analysis of genetic, molecular, and neurobiological mechanisms

  • 期刊论文

  • 发表日期：

    2026年2月7日

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  • Arpan Dhungel,
  • Rinchi Bora

摘要

Purpose of review

This review summarizes the current evidence regarding the role of metabotropic glutamate receptor 5 (mGluR5) in autism spectrum disorder (ASD) integrating genetic, molecular, neuroimaging, and therapeutic evidence to evaluate the mGluR5 related pathways in ASD mechanisms and evaluate its potential as a therapeutic target.

Recent findings

Genetic studies report 25-fold peripheral GRM5 downregulation in ASD patients, with specific variants (rs905646, rs762724) showing biased paternal transmission and associations with increased symptom severity. Advances in super resolution imaging demonstrate that mGluR5 is confined to perisynaptic nanodomains with restricted lateral mobility, forming localized signaling microdomains critical for synaptic modulation. First in-human positron emission tomography (PET) studies using [18F]3-Fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([18F]-FPEB) reveal region specific alterations in mGluR5 availability in ASD, including increased binding in the striatum and thalamus, which correlates inversely with cortical GABA concentrations. In preclinical models, both positive and negative allosteric modulation of mGluR5 has been shown to improve social and repetitive behavioral phenotypes, although these effects are highly contextual and model dependent.

Summary

Collectively, available evidence suggests that dysregulation of mGluR5-associated signaling represents a convergent molecular mechanism in biologically defined subsets of ASD, rather than a universal pathogenic feature. Alterations in synaptic scaffolding complexes (SHANK3–Homer–mGluR5 interactions), receptor trafficking, and activity-dependent protein synthesis may contribute to excitatory/inhibitory imbalance and circuit dysfunction. While preclinical findings support mGluR5 as a therapeutic target, mixed results from clinical trials underscore significant translational challenges. Future therapeutic strategies will require genetically and biologically stratified cohorts, robust pharmacodynamic biomarkers, and multimodal approaches integrating peripheral molecular measures with advanced neuroimaging to refine mGluR5-targeted interventions.

Graphical abstract