Emerging Roles of Microglia in Neuro-vascular Unit: Implications of Microglia-Neurons Interactions.

Zhe Ding,Xianhui Kang,Shengmei Zhu,Lihui Luo,Yueying Zheng,Xiaomin Wu,Shaohui Guo,Shuyuan Gan

doi:10.3389/fncel.2021.706025

Abstract

Microglia, which serve as the defensive interface of the nervous system, are activated in many neurological diseases. Their role as immune responding cells has been extensively studied in the past few years. Recent studies have demonstrated that neuronal feedback can be shaped by the molecular signals received and sent by microglia. Altered neuronal activity or synaptic plasticity leads to the release of various communication messages from neurons, which in turn exert effects on microglia. Research on microglia-neuron communication has thus expanded from focusing only on neurons to the neurovascular unit (NVU). This approach can be used to explore the potential mechanism of neurovascular coupling across sophisticated receptor systems and signaling cascades in health and disease. However, it remains unclear how microglia-neuron communication happens in the brain. Here, we discuss the functional contribution of microglia to synapses, neuroimmune communication, and neuronal activity. Moreover, the current state of knowledge of bidirectional control mechanisms regarding interactions between neurons and microglia are reviewed, with a focus on purinergic regulatory systems including ATP-P2RY12R signaling, ATP-adenosine-A1Rs/A2ARs, and the ATP-pannexin 1 hemichannel. This review aims to organize recent studies to highlight the multifunctional roles of microglia within the neural communication network in health and disease.

Highlights

Research on central nervous system (CNS) disorders has largely concentrated on neurons; an increasing body of research suggests that a purely neurocentral focus is insufficient
In addition to ATP-P2RY12R signaling as described above, a recent study demonstrated that ATP-adenosine-A1Rs signaling in mice suppresses D1 neuronal activity in the striatum, which could be regarded as a novel mechanism for communication between microglia and neurons (Badimon et al, 2020)
We have brought together a series of articles exploring the roles of microglia, including their contributions to synapses, neuroimmune communication, and neuronal activity

Summary

INTRODUCTION

Research on central nervous system (CNS) disorders has largely concentrated on neurons; an increasing body of research suggests that a purely neurocentral focus is insufficient. All cell types in the brain—including neuronal, glial, and vascular components such as endothelia, pericytes, and vascular smooth muscular cells—should be examined in an integrated context (Muoio et al, 2014). Together, these components are termed the neurovascular unit (NVU; Figure 1), which plays an important role in brain function and disease through cell–cell signaling (Iadecola, 2017). Recent studies have shown that the NVU contributes to both stroke and neurodegenerative diseases (Cai et al, 2017; Giaume et al, 2021; Minhas et al, 2021) In light of such findings, increasing research efforts have focused on the NVU as a therapeutic target (Quaegebeur et al, 2011). Microglia-Neurons Interactions depend on soluble factors and intercellular signaling pathways, with the ultimate aim of better understanding the recently recognized functional roles of microglial actions in synaptic function, neuroimmune responses, and regulation of neural activity

A SYNAPTIC ROLE FOR MICROGLIA

CONCLUSIONS AND PERSPECTIVES