Mast Cells Proliferate in the Peri-Hippocampal Space During Early Development and Modulate Local and Peripheral Immune Cells

Brain development is a non-linear process of regionally specific epochs occurring during windows of sensitivity to endogenous and exogenous stimuli. We have discovered an epoch in the neonatal rat brain defined by a transient population of peri-hippocampal mast cells (phMCs) that are abundant from birth through 2-weeks postnatal but absent thereafter. The phMCs are maintained by proliferation and harbor a unique transcriptome compared to mast cells residing in the skin, bone marrow or other brain regions. Pharmacological activation of this population broadly increases blood-brain-barrier permeability, recruits peripheral immune cells and stunts local microglia proliferation. Examination of the post-mortem human brain revealed mast cells in the peri-hippocampal region of a newborn but not an older child, suggesting a similar developmental period exists in humans. Mast cells specifically and early life inflammation generally, have been linked to heightened risk for neurodevelopmental disorders and these results reveal a plausible source of that risk. Overall design: We perfused PN2 and PN7 neonates and dissected the hippocampus, hypothalamus, bone marrow and skin. Each replicate contains cells pooled from 6 animals. We sorted mast cells using flow cytometry for CD45 high, CD11b- and FcERI+ cells. We performed bulk gene RNA-seq of each sample using SMART-Seq v4 UltraLow Input RNA Sequencing.