The "quad-partite" synapse: microglia-synapse interactions in the developing and mature CNS

Abstract

Microglia are the resident immune cells and phagocytes of our central nervous system (CNS). While most work has focused on the rapid and robust responses of microglia during CNS disease and injury, emerging evidence suggests that these mysterious cells have important roles at CNS synapses in the healthy, intact CNS. Groundbreaking live imaging studies in the anesthetized, adult mouse demonstrated that microglia processes dynamically survey their environment and interact with other brain cells including neurons and astrocytes. More recent imaging studies have revealed that microglia dynamically interact with synapses where they appear to serve as "synaptic sensors," responding to changes in neural activity and neurotransmitter release. In the following review, we discuss the most recent work demonstrating that microglia play active roles at developing and mature synapses. We first discuss the important imaging studies that have led us to better understand the physical relationship between microglia and synapses in the healthy brain. Following this discussion, we review known molecular mechanisms and functional consequences of microglia-synapse interactions in the developing and mature CNS. Our current knowledge sheds new light on the critical functions of these mysterious cells in synapse development and function in the healthy CNS, but has also incited several new and interesting questions that remain to be explored. We discuss these open questions, and how the most recent findings in the healthy CNS may be related to pathologies associated with abnormal and/or loss of neural circuits.

Figure 1. Models of microglia-synapse interactions in the CNS

A. In the embryonic and early postnatal brain, microglia are of an amoeboid morphology resembling ‘activated’ cells associated with disease and injury. During this stage, they are actively dividing and recruited to regions throughout the CNS. Fractalkine (purple circles), which may be released by neurons, is proposed to act on fractalkine receptors (purple squares) expressed by microglia to regulate activation, cell number, and/or recruitment to synaptic-enriched regions. DAP12 (orange squares) expressed on the surface of microglia is also thought to affect synapse function during this period, perhaps, by regulating the ‘activation’ state of microglia. B. In the postnatal brain, during the first 3 weeks of postnatal life, microglia, which are still ‘activated’ but now have processes, participate in synaptic pruning. Along with the fractalkine receptor (purple squares) and DAP12 (orange squares), microglia express high levels of complement receptor 3 (CR3, red squares) on their surface. We propose that complement component C3 (red stars) is tagging synapses for removal and have demonstrated that synapses are engulfed by phagocytic microglia in a complement-dependent manner. Disruptions in any of these processes results in deficits in synaptic pruning or maturation. C. In the adult brain, evidence suggests that microglia are releasing soluble factors (grey and black circles) such as BDNF, TNFα, glycine, L-serine etc., which affect basal neurotransmission and synaptic plasticity (i.e., LTP) via direct action on neurons or indirectly via astrocytes (orange). In addition, fractalkine signaling via soluble fractalkine (purple circles), most likely released by neurons, and the fractalkine receptor (purple squares), expressed by microglia, modulates microglia-synapse interactions to affect LTP and behavior in the mature CNS.