Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

Shan, X.; Zhu, T.; Wang, Y.; Shi, T.-T.; Yang, X.; Wang, S.; Zhang, X.; Zhou, W.; Zhou, Z.-Y.; Geng, H.-R.; Yan, J.; Lv, H.; Yan, Y.; Guo, Y.; Shi, L.; Zhang, L.; Hu, K.; Wang, D.; Yu, Y.; Mei, B.; Zhang, Q.; Sun, H.; Wang, X.; Qu, Q.; Zhao, J.-Y.; Li, W.-G.; Li, F.

doi:10.64898/2026.10.14.759089

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bioRxiv · 10.64898/2026.10.14.759089

Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

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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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Shan, X., Zhu, T., Wang, Y., Shi, T.-T., Yang, X., Wang, S., Zhang, X., Zhou, W., Zhou, Z.-Y., Geng, H.-R., Yan, J., Lv, H., Yan, Y., Guo, Y., Shi, L., Zhang, L., Hu, K., Wang, D., Yu, Y., Mei, B., Zhang, Q., Sun, H., Wang, X., Qu, Q., Zhao, J.-Y., Li, W.-G., Li, F.. 2026-10-16. Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior. https://doi.org/10.64898/2026.10.14.759089

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