A unique peri-hippocampal mast cell population drives neurodevelopment

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Project Summary The etiology of neurodevelopmental diseases such as autism spectrum disorder and schizophrenia is multifactorial, with increasing evidence indicating a role for immune cells such as microglia and peripheral immune cells. Understanding how the immune system regulates critical periods in brain development is important for a thorough comprehension of disease progression. While resident myeloid cells microglia can support cell genesis, synapse formation, and myelination, less clear is the contribution of peripheral immune cells to these phenomena. This includes mast cells (MCs), a type of innate immune cell that degranulates to release mediators including histamine, cytokines, growth factors, and more in the settings of allergy, inflammation, and tissue repair. We have discovered a robust population of MCs lining the lateral ventricles next to the hippocampus in the rat. This population rises in number and peaks at postnatal day 7, then decreases so that MCs are undetectable by week 3, reminiscent of a developmental critical period. The presence of these highly reactive immune cells, associated with allergic and parasitic diseases, in a tightly regulated developmental space raises questions about their physiological purpose in this niche at this time. The first two weeks of neurodevelopment mark the beginning and expansion of hippocampal neurogenesis, axon outgrowth, and synaptogenesis, all of which are impacted by immune signaling. Additionally, links between diseases with an overabundance of MCs (e.g., mastocytosis) and autism point to a potential pathological role for MCs in neurodevelopment. This proposal seeks to decipher the role of peri-hippocampal MCs during a critical period in hippocampal development. Importantly, these MCs are replicative, unlike most tissue-resident MCs, and do not originate from peripheral bone marrow sources. I hypothesize that these MCs originate from the embryonic yolk sac and seed the brain in embryogenesis, similarly to microglia. An inducible Cre fate-mapping system combined with flow cytometry will test this hypothesis in mice (Aim 1.1), followed by RNAscope for candidate yolk sac genes in rats (Aim 1.2), bringing this investigation back to our original rat model. Preliminary RNAseq analysis on these MCs uncovered gene ontology terms related to processes such as neuronal projection and synapse formation, informing our hypothesis that these MCs participate in hippocampal synaptogenesis. In the preoptic area, MCs alter synaptic patterning via histamine release, a viable strategy that we will explore by inducing peri-hippocampal MC degranulation and determining the effect on dentate gyrus dendritic spine density in Aim 2. These experiments will help decipher the role of MCs in hippocampal neurodevelopment, providing another piece in the puzzle of neuroimmune interactions during development. Completion of these experiments, as well as mentorship from developmental neuroscientist Dr. Margaret McCarthy and allergy immunologist Dr. Achsah Keegan, will provide comprehensive training in neuroimmunology and establish a strong foundation for a physician-scientist career in pediatric neurology.