Understanding microglial diversity and implications for neuronal function in health and disease

Abstract

Genetic data implicate microglia as central players in brain health and disease, urging the need to better understand what microglia do in the brain. Microglia are critical partners in neuronal wiring and function during development and disease. Emerging literature suggests that microglia have diverse functional roles, raising the intriguing question of which functions of microglia become impaired in disease to undermine proper neuronal function. It is also becoming increasingly clear that microglia exist in heterogeneous cell states. Microglial cell states appear context-dependent, that is, age, sex, location, and health of their microenvironment; these are further influenced by external signaling factors including gut microbiota and lipid metabolites. These data altogether suggest that microglia exist in functional clusters that impact, and are impacted by, surrounding neuronal microenvironment. However, we still lack understanding of how we can translate microglia cell states into function. Here, we summarize the state-of-the-art on the diverse functions of microglia in relation to neuronal health. Then, we discuss heterogeneity during developing, healthy adult and diseased brains, and whether this may be predetermined by origin and/or regulated by local milieu. Finally, we propose that it is critical to gain high-resolution functional discernment into microglia-neuron interactions while preserving the spatial architecture of the tissue. Such insight will reveal specific targets for biomarker and therapeutic development toward microglia-neuron crosstalk in disease.

Keywords: Alzheimer's disease; microglia; neuro-immune crosstalk; synapse; transcriptional heterogeneity.

FIGURE 1

Microglia impact neuronal homeostasis and function. Figure illustrating microglia‐neuron crosstalk in the CNS. Microglia sense their neural environment by proteins encoded by sensome genes, crucial to maintain CNS homeostasis, and rapidly respond to damage or insult. Once excess neural progenitors or debris are detected, microglia initiate their clearing functions via TREM2, CR3 (DAP12), AXL, MER, and other yet‐to‐be‐defined molecules. Additionally, microglia sculpt and refine neural circuits by pruning synapses during specific developmental windows through the complement signaling pathway, fractalkine/ADAM10 signaling, and TREM2‐mediated pathways. Microglia also actively “listen” to adjacent neuronal activity by P2Y12, GABA‐R, β2AR, AchR, and other neurotransmitter receptors

FIGURE 2

Microglia cell states in adulthood: does postcode matter? Transcriptomic analyses of microglia isolated from different brain regions support the existence of region‐specific functional cell states. Dependent on their local microenvironment or “residential postcode,” microglia acquire functional phenotypes that support local neuronal development and function. GO biological processes are based on enriched transcripts of microglia residing in that particular region (Ayata et al., ; De Biase et al., ; Grabert et al., 2016)