Tuning neural circuits and behaviors by microglia in the adult brain

Abstract

Microglia are the primary immune cells of the CNS, contributing to both inflammatory damage and tissue repair in neurological disorder. In addition, emerging evidence highlights the role of homeostatic microglia in regulating neuronal activity, interacting with synapses, tuning neural circuits, and modulating behaviors. Herein, we review how microglia sense and regulate neuronal activity through synaptic interactions, thereby directly engaging with neural networks and behaviors. We discuss current studies utilizing microglial optogenetic and chemogenetic approaches to modulate adult neural circuits. These manipulations of microglia across different CNS regions lead to diverse behavioral consequences. We propose that spatial heterogeneity of microglia-neuron interaction lays the groundwork for understanding diverse functions of microglia in neural circuits and behaviors.

Keywords: chemogenetics; microglial heterogeneity; neurogenesis; neuroimmune interaction; optogenetics; synaptic plasticity.

Figure 1.. A U-shaped pattern of microglia responses for sensing and regulating neuronal activity.

Compared with the basal awake state, hyperactive neurons (upper right) increase ATP release and promote microglial process interaction through microglial P2Y12 receptors. The CD39 and CD73 ectoenzymes on microglia rapidly hydrolyze ATP/ADP into adenosine (ADO), which subsequently reduces neural firing by binding to the adenosine A1 receptor (A1R, bottom right). Under awake condition, adrenergic terminals release norepinephrine (NE) to induce microglia process retraction through microglial β₂-adrenoreceptor (Bottom middle). Concordantly, hypoactive neurons (upper left) increase microglial process dynamics due to the low tonic NE level and disinhibition of β₂-adrenoreceptor-mediated process retraction. Under this condition, microglial processes can enter the synaptic cleft to shield inhibitory inputs and promote neural activity (bottom left).

Figure 2.. Homeostatic microglia actively shape adult neural circuits.

Microglia modulate synaptic plasticity and adult neurogenesis in the healthy brain. (A) In the cortex, BDNF signaling released by microglia promotes synapse formation and enhances synaptic transmission. (B) Additionally, microglia interact with dendritic spines, thereby increasing synapse activity and enhancing local cortical network synchronization. (C) In the hippocampal CA1 region, microglia physically contact dendritic shafts and postsynaptic spines. Higher contact frequency correlates with more spine formation and elimination. (D) In the dentate gyrus (DG), microglia phagocytose ECM components through interleukin 33 (IL-33) signaling to promote spine formation and functional plasticity. (E) Microglia in the DG actively remove apoptotic newborn neurons but also promote adult neurogenesis. (F) In the olfactory bulb (OB) and DG, microglia prune synapses on adult-born neurons depending on the presence of phosphatidylserine (PS).

Figure 3.. Consequences of microglial manipulations on neural circuits and behaviors.

(A) Optogenetic activation of spinal microglia using the red-activatable ChR variant (ReaChR) increases Ca2⁺-dependent IL-1β release. Microglia-released IL-1β promotes neural activity and induces chronic pain in mice [76]. (B) Optogenetic activation of channelrhodopsin 2 (ChR2) on Hoxb8 microglia within the striatum (STR), the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP), or basolateral amygdala (BLA) transiently increases local network activity, inducing grooming or anxiety-like behaviors in mice [80]. (C) Chemogenetic activation of microglial Gq-DREADD in the striatum reduces excitability of medium spiny neurons via microglial-released prostaglandins. Microglial Gq-DREADD activation induces a negative affective state characterized by anhedonia and aversion in mice [107].