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PreprintCC BY-NC-NDbioRxiv

Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

  • X. Shan
  • T. Zhu
  • Y. Wang
  • T.-T. Shi
  • X. Yang
  • S. Wang
  • X. Zhang
  • W. Zhou
  • Z.-Y. Zhou
  • H.-R. Geng
  • J. Yan
  • H. Lv
15 more authors
  • Y. Yan
  • Y. Guo
  • L. Shi
  • L. Zhang
  • K. Hu
  • D. Wang
  • Y. Yu
  • B. Mei
  • Q. Zhang
  • H. Sun
  • X. Wang
  • Q. Qu
  • J.-Y. Zhao
  • W.-G. Li1
  • F. Li1
  1. 1Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
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Abstract

Branched-chain amino acid metabolism is linked to neurodevelopmental disorders, but whether a defined amino acid directly modulates cortical receptor signaling to control behavior is unknown. Here, we show that valine is uniquely required for sociability through medial prefrontal cortex (mPFC) circuitry. Partial dietary valine restriction, but not comparable leucine or isoleucine restriction, or mPFC-restricted acceleration of BCAA catabolism through Bckdk loss, disrupts social interaction, and local valine supplementation rescues behavior. LiP-SMap, surface plasmon resonance, cryo-EM, and mutagenesis identify metabotropic glutamate receptor 5 (mGluR5) as a direct valine target and reveal a valine-selective allosteric pocket distinct from the glutamate site. Valine is signaling-biased: it drives {beta}-arrestin-linked output yet has little standalone Gq efficacy, instead potentiating glutamate-evoked mGluR5 signaling to recruit endocannabinoid/CB1 feedback, gate inhibitory transmission, and preserve mPFC-dependent social behavior. Together, these findings identify valine as a diet-derived allosteric ligand that links amino acid availability to cortical circuit control of social behavior.

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Cite

BibTeXRIS
BibTeX
@misc{shan2026valine,
  title = {{Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior}},
  author = {X. Shan and T. Zhu and Y. Wang and T.-T. Shi and X. Yang and S. Wang and X. Zhang and W. Zhou and Z.-Y. Zhou and H.-R. Geng and J. Yan and H. Lv and Y. Yan and Y. Guo and L. Shi and L. Zhang and K. Hu and D. Wang and Y. Yu and B. Mei and Q. Zhang and H. Sun and X. Wang and Q. Qu and J.-Y. Zhao and W.-G. Li and F. Li},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.14.759089},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.14.759089v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior
AU  - X. Shan
AU  - T. Zhu
AU  - Y. Wang
AU  - T.-T. Shi
AU  - X. Yang
AU  - S. Wang
AU  - X. Zhang
AU  - W. Zhou
AU  - Z.-Y. Zhou
AU  - H.-R. Geng
AU  - J. Yan
AU  - H. Lv
AU  - Y. Yan
AU  - Y. Guo
AU  - L. Shi
AU  - L. Zhang
AU  - K. Hu
AU  - D. Wang
AU  - Y. Yu
AU  - B. Mei
AU  - Q. Zhang
AU  - H. Sun
AU  - X. Wang
AU  - Q. Qu
AU  - J.-Y. Zhao
AU  - W.-G. Li
AU  - F. Li
PY  - 2026
DA  - 2026/10/14
PB  - bioRxiv
DO  - 10.64898/2026.10.14.759089
UR  - https://www.biorxiv.org/content/10.64898/2026.10.14.759089v1
AB  - Branched-chain amino acid metabolism is linked to neurodevelopmental disorders, but whether a defined amino acid directly modulates cortical receptor signaling to control behavior is unknown. Here, we show that valine is uniquely required for sociability through medial prefrontal cortex (mPFC) circuitry. Partial dietary valine restriction, but not comparable leucine or isoleucine restriction, or mPFC-restricted acceleration of BCAA catabolism through Bckdk loss, disrupts social interaction, and local valine supplementation rescues behavior. LiP-SMap, surface plasmon resonance, cryo-EM, and mutagenesis identify metabotropic glutamate receptor 5 (mGluR5) as a direct valine target and reveal a valine-selective allosteric pocket distinct from the glutamate site. Valine is signaling-biased: it drives {beta}-arrestin-linked output yet has little standalone Gq efficacy, instead potentiating glutamate-evoked mGluR5 signaling to recruit endocannabinoid/CB1 feedback, gate inhibitory transmission, and preserve mPFC-dependent social behavior. Together, these findings identify valine as a diet-derived allosteric ligand that links amino acid availability to cortical circuit control of social behavior.
ER  -