Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling PMID: 38168932

ADC Targets in Oncology

2026-04-10

Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling

Nat Neurosci. 2024 Jan 2. doi: 10.1038/s41593-023-01515-0.

Dongdong Zhang ¹ ² ³ ⁴ ⁵ , Jiayu Ruan ² ³ ⁴ ⁵ , Shiyu Peng ² ⁴ , Jinze Li ² ³ ⁴ ⁵ , Xu Hu ² ³ ⁴ ⁵ , Yiyi Zhang ² ³ ⁴ ⁵ , Tianrui Zhang ⁵ , Yaping Ge ² ³ ⁴ ⁵ , Zhu Zhu ² ³ ⁴ ⁵ , Xian Xiao ² ³ , Yunxu Zhu ⁵ , Xuzhao Li ² ³ ⁴ ⁵ , Tingbo Li ² ³ ⁴ ⁵ , Lili Zhou ² ³ ⁴ ⁵ , Qingzhu Gao ⁵ , Guoxiao Zheng ³ , Bingrui Zhao ² ³ ⁴ ⁵ , Xiangqing Li ⁶ , Yanming Zhu ⁷ ⁸ , Jinsong Wu ⁹ ¹⁰ ¹¹ ¹² ¹³ , Wensheng Li ¹⁴ , Jingwei Zhao ¹⁵ , Woo-Ping Ge ¹⁶ , Tian Xu ² ⁴ , Jie-Min Jia ¹⁷ ¹⁸ ¹⁹ ²⁰

Affiliations

1. School of Life Sciences, Fudan University, Shanghai, China.
2. Key Laboratory of Growth Regulation and Translation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
3. Laboratory of Neurovascular Biology, Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China.
4. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
5. Laboratory of Neurovascular Biology, School of Life Sciences, Westlake University, Hangzhou, China.
6. College of Artificial Intelligence and Big Data for Medical Sciences, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, China.
7. Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
8. Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, MA, USA.
9. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
10. Brain Function Laboratory, Neurosurgical Institute of Fudan University, Shanghai, China.
11. Institute of Brain-Intelligence Technology, Zhangjiang Lab, Shanghai, China, Shanghai, China.
12. Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China.
13. Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China.
14. Department of Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
15. Department of Anatomy, Histology, and Embryology, Research Center of Systemic Medicine, School of Basic Medicine, and Department of Pathology of the Sir Run-Run Shaw Hospital, The Cryo-EM Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
16. Chinese Institute for Brain Research, Beijing, Beijing, China.
17. Key Laboratory of Growth Regulation and Translation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. [email protected].
18. Laboratory of Neurovascular Biology, Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. [email protected].
19. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. [email protected].
20. Laboratory of Neurovascular Biology, School of Life Sciences, Westlake University, Hangzhou, China. [email protected].

Abstract

Neurovascular coupling (NVC) is important for brain function and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in NVC, how active neural information is conveyed to the targeted arterioles in the brain remains poorly understood. Here, using two-photon focal optogenetics in the mouse cerebral cortex, we demonstrate that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural-arteriolar smooth muscle cell junctions (NsMJs). The presynaptic parental-daughter bouton makes dual innervations on postsynaptic dendrites and on arteriolar smooth muscle cells (aSMCs), which express many types of neuromediator receptors, including a low level of glutamate NMDA Receptor subunit 1 (Grin1). Disruption of NsMJ transmission by aSMC-specific knockout of GluN1 diminished optogenetic and whisker stimulation-caused functional hyperemia. Notably, the absence of GluN1 subunit in aSMCs reduced brain atrophy following cerebral ischemia by preventing CA²⁺ overload in aSMCs during arteriolar constriction caused by the ischemia-induced spreading depolarization. Our findings reveal that NsMJ transmission drives NVC and open up a new avenue for studying stroke.