Year: 2026
Type: preprint
Abstract: SUMMARY 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 β-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. Graphical abstract In Brief Valine, an essential amino acid, directly engages an allosteric pocket in mGluR5 and biases receptor signaling in the medial prefrontal cortex. By potentiating glutamate-driven mGluR5–endocannabinoid suppression of inhibition, valine preserves excitation–inhibition balance and social behavior. Highlights Valine is uniquely required in mPFC to support sociability. LiP-SMap, SPR, and cryo-EM identify a valine pocket in mGluR5. Valine biases mGluR5 signaling and potentiates glutamate-evoked output. Valine–mGluR5 recruits CB1 feedback to gate inhibition during behavior.
Authors: Xingyue Shan, Tailin Zhu, Yuwei Wang, Tian-Tian Shi, Xiaoyu Yang, Susu Wang, Xin Zhang, Wei Zhou, Zeyu Zhou, Haoran Geng, Jiangyu Yan, Hui Lv, Yuhua Yan, Yue Guo, Lan Shi, Lingli Zhang, Keyi Hu, Dandan Wang, Ye Yu, Bing Mei, Qianlong Zhang, Haipeng Sun, Xiaoqun Wang, Qianhui Qu, Jian-Yuan Zhao, Wei-Guang Li, Fei Li
Institutions: Shanghai Jiao Tong University, XinHua Hospital, East China Normal University, Shanghai Medical College of Fudan University, Fudan University, Shanghai Stomatological Hospital, Huashan Hospital, Frontiers Center for Brain Science of the Ministry of Education, China Pharmaceutical University, State Key Laboratory of Natural Medicine, Lanzhou University, Tianjin Medical University, Chinese Academy of Sciences, Beijing Normal University, Institute of Biophysics, State Key Laboratory of Brain and Cognitive Science, Changping Laboratory
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: Innovative Research Team of High-level Local University in Shanghai, Shanghai Municipal Health Commission, National Natural Science Foundation of China, China Postdoctoral Science Foundation, Shanghai Education Development Foundation, Shanghai Municipal Education Commission, Science and Technology Commission of Shanghai Municipality, Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University
Awards: G1124904482, G1607740230, G1620426753, G1806467789, G2040955015, G2889423598, G3125680708, G3553409514, G3891868918, G4026589909, G4226030509, G4235736369, G4238415842, G4612595535, G4694277903, G5704653500, G6271259443, G6851881289, G7330545098, G7648398611, G7795230133, G8419687357, G978627347
OpenAlex ID: W7222745068