Mast Cell Modulation of the Developing Hippocampus

Abstract

Brain development requires orchestration of overlapping critical periods defined by responsiveness to endogenous or exogenous stimuli (i.e. hormones, light, touch). Simultaneously, sensitive periods represent heightened risk to perturbations by abnormal stimuli (i.e. inflammation). Though neuro-immune cooperation between resident microglia and neurons is essential during critical periods of brain development, the contribution of infiltrating immune cells to neurodevelopmental processes is largely elusive. We discovered a critical and sensitive period created by a population of peri-hippocampal mast cells (phMCs) in the lateral ventricles abundant from birth through 2-weeks-old in the neonatal rat but absent thereafter. This epoch of phMCs is maintained by self-replication inside the brain, creating a mix of mature and immature mast cells which constitutively piecemeal degranulate. phMCs harbor a unique transcriptomic identity to skin, bone marrow and other brain mast cells including transcripts encoding colony-stimulating factors (Csf1, Csf2) essential for microglial development. Pharmacological inhibition of phMC degranulation and secretion stunts microglial maturation, illuminating the role of phMC-derived factors in driving hippocampal microglial development. In contrast, activation of phMCs releases proinflammatory chemokines, compromises the blood-brain-barrier (BBB), and recruits peripheral immune cells across the CNS for at least two days. Together, these findings indicate that a transient population of peri-hippocampal mast cells creates a critical period for microglial maturation via piecemeal degranulation in the healthy brain and a sensitive period to inflammatory stimuli. The dual role of phMCs in homeostasis and inflammation highlight an essential need to understand how the immune system can adapt its function to serve neuronal populations and prevent inflammatory disturbances that lead to neurologic disease.