Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning

Abstract

Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits. In brain physiology, highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli. Once the brain switches its functional states, microglia are recruited to specific sites to exert their immune functions, including the release of cytokines and phagocytosis of cellular debris. The crosstalk of microglia between neurons, neural stem cells, endothelial cells, oligodendrocytes, and astrocytes contributes to their functions in synapse pruning, neurogenesis, vascularization, myelination, and blood-brain barrier permeability. In this review, we highlight the neuron-derived "find-me," "eat-me," and "don't eat-me" molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development. This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease, thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.

Figure 1

A schematic process of synapse formation and elimination. Briefly, synapse formation is initiated through the contact of axons and dendrites. The synapses are further established by the rapid expression of essential assembling proteins and are functionally connected through the induction of synaptic plasticity. Synapses are finally stabilized via the elimination of weaker synapses through microglial phagocytosis. Created with BioRender.com. AMPAR: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; Gln: glutamine; Glu: glutamate; mGluR1/5: metabotropic glutamate receptor type 1/5; mGluR2: metabotropic glutamate receptor type 2; NMDAR: N-methyl-D-aspartatic acid receptor; Snare: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; VGLUT: vesicular glutamate transporter.

Figure 2

Microglial process in synaptic pruning. (i) Neurons secrete distinct find-me signals to recruit microglia toward the immature synapses. (ii) Less active synapses and immature synapses are tagged by eat-me signals phosphatidylserine or complement proteins, which can be recognized by the various receptors (CR3, GPR56, TREM2, integrin αvβ5, MERTK) expressed on the microglia. Synaptic pruning occurs through the direct binding-mediated microglial engulfment of tagged synapses. (iii) Microglial phagocytosis is also regulated by don’t eat-me signals including classical complement pathway inhibitors (SRPX2, Csmd1, Nptx2); CD47-SIRPα; and neuronal polysialylated protein-mediated interaction with CD22 and CD33 to block microglial process. Created with BioRender.com. ATP: Adenosine triphosphate; CD22: Siglec-2; CD33: Siglec-3; CD47: cluster of differentiation 47; CR3: complement 3 receptor; CX3CL1: C-X3-C motif chemokine ligand 1; GABA: γ-aminobutanoic acid; GPR56: G-protein coupled receptor; MERTK: MER proto-oncogene tyrosine kinase; PS: phosphatidylserine; SIRPα: signal regulatory protein α; SRPX2: sushi repeat-containing protein X-linked 2; TREM2: triggering receptor expressed on myeloid cells-2.

Figure 3

Other important immune signals modulate microglia-mediated synaptic pruning, including the CX3CL1-CX3CR1, IL-33-ST2, JAK2-STAT1, and DAP12-TREM2-mediated signaling. Created with BioRender.com. CX3CL1: C-X3-C motif chemokine ligand 1; CX3CR1: C-X3-C motif chemokine receptor 1; DAP12: TYRO protein tyrosine kinase binding protein; IL-33: interleukin 33; JAK2: Janus kinase 2; ST2: interleukin 33 receptor; STAT1: signal transducer and activator of transcription 1; TREM2: triggering receptor expressed on myeloid cells-2.