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The axon initial segment-associated microglia regulate neuronal activity and visual perception

Yaping Wang^1,† , Qiushi Wang^1,† , Chen Gao¹ , Shu He¹ , Cheng Wei¹ , Jia Song¹ , Xinli Liu² , Xiaoli Liu¹ , Shi Feng¹ , Wen Yao¹ , Wen Wu² , Tian-Ming Gao¹ , Siqiang Ren^1,2,*

¹Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence; State Key Laboratory of Multi-organ Injury Prevention and Treatment; Key Laboratory of Mental Health of the Ministry of Education; Guangdong Province Key Laboratory of Psychiatric Disorders; Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases; Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders; Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
²Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
^†These authors contributed equally: Yaping Wang, Qiushi Wang
* Correspondence: Siqiang Ren(rensiqiang159@smu.edu.cn)

As innate immune cells in the brain, microglia directly contact excitatory neurons and regulate their activities under various conditions; however, the mechanisms of direct microglia–neuron functional interactions remain largely unknown. Here, we identified one special population of neocortical microglia that specifically associate with the axon initial segments (AISs) of excitatory neurons, and could regulate their activities and contribute to visual perception. We found that brief depolarization of AIS-associated microglia, but not the AIS-non-associated microglia, significantly promoted the action potential firing of related excitatory neurons, which relied mechanistically on microglial K+ release through the outward K+ channel THIK-1. Interestingly, in vivo visual stimulation with drifting gratings evoked microglial transient depolarizations specifically on the processes, which depended on muscarinic receptors and triggered K+ release through THIK-1; meanwhile, visual stimulation induced more robust calcium responses in neurons associated with microglia at their AISs compared with nearby unassociated neurons. Disruption of the AIS–microglia interaction disturbed calcium responses specifically in neurons associated with microglia at their AISs, impaired the coordinated activity of the entire neural ensemble, and thereby affected the visual discrimination behavior of awake mice. Collectively, our findings identified a new type of microglia–neuron functional interaction that may be critical for higher-order brain functions.

https://doi.org/10.1038/s41422-026-01218-8

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