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.

Neuronal-glial populations form functional networks in a biocompatible 3D scaffold

“…This is particularly interesting when the astrocyte morphology seen in 3D culture (extensive, intricate processes) was more consistent with astrocyte morphology in vivo than with that seen in comparator 2D monolayer cultures, as previously described [14]. However, given growing recognition of the 'quadpartite synapse' [12], investigations of microglia in 3D scaffolds such as Alvetex are warranted.…”

Sex and regional differences in microglia morphology and complement receptor 3 are independent of constitutive neuroinflammatory protein concentrations in healthy mice

“…The CR3 ligands that are important to brain physiology/pathophysiology include lipopolysaccharide [LPS, (Wright and Jong, 1986)], C3b/iC3b (Beller et al, 1982), fibrinogen (Wright et al, 1988), and high mobility group box protein 1 (HMGB-1). CR3-ligand interactions initiate cell chemotaxis or phagocytosis, and complement-mediated phagocytosis is a key component of brain development and adult physiology (Schafer et al, 2013). In the adult healthy brain, synaptic pruning is proposed via C3b-opsoinized synapses (Stevens et al, 2007;Tremblay et al, 2011) as neuronal and synaptic activity changes-a phenomenon that may disproportionally occur according to sex and estrus cycle (Crain and Watters, 2010).…”

La microglie : des cellules immunitaires qui sculptent et contrôlent les synapses neuronales

“…Nous verrons plus loin un autre exemple de la mise en jeu de cette triade microglie-astrocyte-neurone. qui ont amené certains auteurs à proposer la notion de synapse quadripartite [8], dans laquelle la microglie serait le quatrième partenaire.…”