Microglial Dynamics During Human Brain Development

Abstract

Microglial cells are thought to colonize the human cerebrum between the 4th and 24th gestational weeks. Rodent studies have demonstrated that these cells originate from yolk sac progenitors though it is not clear whether this directly pertains to human development. Our understanding of microglial cell dynamics in the developing human brain comes mostly from postmortem studies demonstrating that the beginning of microglial colonization precedes the appearance of the vasculature, the blood-brain barrier, astrogliogenesis, oligodendrogenesis, neurogenesis, migration, and myelination of the various brain areas. Furthermore, migrating microglial populations cluster by morphology and express differential markers within the developing brain and according to developmental age. With the advent of novel technologies such as RNA-sequencing in fresh human tissue, we are beginning to identify the molecular features of the adult microglial signature. However, this is may not extend to the much more dynamic and rapidly changing antenatal microglial population and this is further complicated by the scarcity of tissue resources. In this brief review, we first describe the various historic schools of thought that had debated the origin of microglial cells while examining the evidence supporting the various theories. We then proceed to examine the evidence we have accumulated on microglial dynamics in the developing human brain, present evidence from rodent studies on the functional role of microglia during development and finally identify limitations for the used approaches in human studies and highlight under investigated questions.

Keywords: brain development; glial cells; human brain; microglia; neurodevelopment; proliferation.

Figure 1

Timeline of human microglial development. This figure places microglial entry into developing brain areas in the context of the approximate co-occurrence of cortical developmental events. Microglia are detected in the amoeboid state in the telencephalic ventricular, intermediate, and MZs and not the cortical plate at 4.5 weeks of gestation; microglia are detected in the ramified state in the hindbrain by 6 weeks; amoeboid microglia are detected in the SC by 9 weeks of gestation; the density of amoeboid microglia is highest in the mesencephalon (midbrain) by 22 weeks of gestation. The relevant references to each process are included (, , , , , –45, 47, 48, 54, 60, 63, 64, 70, 91, 106). *Two barriers are included here: the BBB proper at the level of the endothelium of the cerebral blood vessels and the blood–CSF barrier at the level of the choroid plexus epithelial cells. The CSF–brain barrier is detected as early as 16 days through the appearance of strap junctions and is not shown on the timeline. Abbreviations: BBB, blood–brain barrier; BM, bone marrow; CSF, cerebrospinal fluid; IZ, intermediate zone; MZ, marginal zone; PCD, post conceptional days; GW, gestational week; SC, spinal cord; YS, yolk sac.