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

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.