Fetal brain response to maternal inflammation requires microglia
Preprint posted on 22 February 2024 https://www.biorxiv.org/content/10.1101/2024.02.21.581282v1#:~:text=These%20findings%20demonstrate%20that%20microglia,a%20potential%20therapeutic%20cell%20target.
Microglia connect maternal immune activation to adverse fetal brain development
Selected by Manuel Lessi
Categories: cell biology, evolutionary biology, immunology, molecular biology, neuroscience
1. Introduction
Fetal brain development is an extremely sensitive and protracted process that relies on properly orchestrated molecular and cellular events (1). Disruption in such processes can (among many other things) be causative of psychiatric conditions (2). The delicate homeostasis required can be disrupted by Maternal Immune Activation (MIA) following infection and inflammation affecting the mother during gestation. Indeed several studies have linked MIA to a wide range of neurodevelopmental disorders (3).
Microglia (MG), the immune residents of the central nervous system, are known to play a role in such processes, but there is still confusion regarding the molecular and cellular events underlying MIA-induced developmental neurotoxicity. Also, we lack a broad understanding of how microglia mature and change through neurodevelopment. In this context, single cell genomics unlocks the possibility to investigate molecular mechanisms altered by environmental risk factors in specific cellular populations within the developing brain.
In this study, the authors made clever use of a mouse model of MIA by coupling it with high content single cell-RNA sequencing. It allowed them pinpoint microglia as being responsible for mediating maternal infections and the deleterious effects on fetuses’ brain at critically sensitive life stages. Moreover, the authors generated a comprehensive atlas revealing the molecular state of microglia across mouse development at single cell resolution.
2. Main results
2.1 Microglia mediate MIA in the developing mouse brain
To causally link microglia to immune activation in the brain, the authors used a mouse model genetically encoded to lack Csf1r, a gene whose expression is necessary for the survival, proliferation, and differentiation of many myeloid cell lineages.
Both wildtype (WT) and Csf1r knockout pregnant dams were injected with Poly (I:C) to stimulate MIA or with saline which served as a negative control. Animals were sacrificed 72h after the treatment and fetal cerebral cortexes were subjected to single nuclei isolation and RNA sequencing at a relevant developmental stage (E15.5) (Fig.1).
Figure 1: Schematic of experimental design adopted to causally link microglia as the mediator of MIA effects in fetal brain. Created with BioRender.com
When comparing the results obtained from these four groups, these relevant insights emerged:
• Mice lacking microglia developed normal brains.
• MIA did not alter the non-microglia cell type proportion in both mouse models.
• MIA led to significant gene expression changes across multiple cell types in the developing cortex.
• Eliminating microglia via a Csf1r knockout abolished most of these effects.
• MIA in the presence, but not absence, of microglia induced widespread down-regulation in expression of genes involved in cell proliferation, energy metabolism, and protein catabolism.
Interestingly, only in wildtype animals neurons had their transcriptome modulated, including genes relevant for neurodevelopmental disorders. These insights prove that microglia is required for mediating MIA effects on embryonic neurodevelopment.
2.2 A molecular atlas of microglia during mouse neurodevelopment.
To further dissect the role of microglia in the developing mouse brain, Ostrem and colleagues also performed scRNA-seq on microglia isolated by FACS sorting across mouse neurodevelopment, sampling seven timepoints spanning from embryonic day 12.5 to postnatal day 1.
This atlas is an extremely powerful resource charting a map that portrays molecular states and transcriptional programs adopted by microglia during development. The atlas will also be instrumental in future research to help navigate complex microglia’ neurodevelopmental trajectories in both physiological and pathological settings.
2.3 Prenatal MIA induces long-lasting transcriptional effects on microglia
To better understand which transcriptional changes are specifically modulated by MIA in microglia, wildtype dams were subjected to MIA at E 12.5.scRNA-seq was then performed after 24h, 72h and at postnatal day 14 on more than 50,000 isolated immune brain cells.
While 24h after injection microglia displayed a gene signature pointing to immune activation and chemotaxis, the transcriptome of isolated microglia was suggesting energetic reprogramming among all the detected states captured by the analysis after 72h. Of note, microglia in juvenile mouse offspring experienced protracted gene expression shifts ascribable to an impaired capacity for activation and phagocytosis.
3. Conclusion/why I highlight this preprint
I really enjoyed delving into this preprint and these are the key points I enjoyed the most:
• The authors uncover microglia as the only mediator of noxious neurological MIA impacts.
• The presented results are very robust and confirmed with orthogonal experimental approaches.
• The generated microglia cell atlas is a wonderful resource that will empower new research in the field.
• This work demonstrates the unique ability of single cell genomics to disentangle complex cellular states in a heterogeneous tissue such as the brain
4. Questions/future directions
• ScRNA-seq analysis yielded novel insights into microglia as mediators of MIA. Do you plan to perform any immunostaining for canonical brain markers, to investigate cytoarchitectural alterations induced in this context?
• Do you plan to perform behavioral tests on mice that underwent prenatal MIA to see if there are traces of autism-like phenotypes?
• The mouse is a useful biological model, yet it fails to recapitulate key features of human neurodevelopment (4). Have you considered validating these results in other biological systems such as brain organoids co-cultured with microglia?
5. References
1. Zhou, Y., Song, H. & Ming, G. Genetics of human brain development. Nat. Rev. Genet. 1–20 (2023) doi:10.1038/s41576-023-00626-5.
2. Cheroni, C., Caporale, N. & Testa, G. Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology. Mol. Autism 11, 69 (2020).
3. Han, V. X., Patel, S., Jones, H. F. & Dale, R. C. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat. Rev. Neurol. 17, 564–579 (2021).
4. Zhao, X. & Bhattacharyya, A. Human Models Are Needed for Studying Human Neurodevelopmental Disorders. Am. J. Hum. Genet. 103, 829–857 (2018).
Posted on: 24 April 2024 , updated on: 25 April 2024
doi: https://doi.org/10.1242/prelights.37191
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