Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function

Abstract

Innate immune cells play a well-documented role in the etiology and disease course of many brain-based conditions, including multiple sclerosis, Alzheimer's disease, traumatic brain and spinal cord injury, and brain cancers. In contrast, it is only recently becoming clear that innate immune cells, primarily brain resident macrophages called microglia, are also key regulators of brain development. This review summarizes the current state of knowledge regarding microglia in brain development, with particular emphasis on how microglia during development are distinct from microglia later in life. We also summarize the effects of early life perturbations on microglia function in the developing brain, the role that biological sex plays in microglia function, and the potential role that microglia may play in developmental brain disorders. Finally, given how new the field of developmental neuroimmunology is, we highlight what has yet to be learned about how innate immune cells shape the development of brain and behavior.

Keywords: behavior; brain development; early life stress; inflammation; microglia; neurodevelopmental disorders; sex differences; synaptic pruning.

Figure 1

Overview of microglia during brain development. (A) illustrates the developmental time points when microglia colonize and proliferate in the developing brain, beginning on embryonic day (E) 8.5. Microglia numbers peak in the rodent brain at postnatal day (P) 14 following local proliferation. Microglia then either die back or migrate from region to region until adult numbers are reached by P28. (B) indicates the different phenotypes of microglia across development based on unique gene expression patterns, listed in parentheses, and somewhat distinct morphologies. The brackets refer back to the developmental timeline depicted above in (A). (C) summarizes our current state of knowledge regarding which processes of development microglia have been shown to regulate, as well as the molecular factors involved. The brackets refer back to the developmental timeline depicted above in (A), illustrating when research to date has shown that microglia are involved in a given process. These data do not preclude the (likely) possibility that microglia regulate each developmental process beyond the time window indicated, but represent our current state of knowledge. Table 1 lists the publications that were used to design (C).