Peri-Hippocampal Mast Cells Regulate Hippocampal Neurogenesis and Blood-Brain Barrier Permeability During Early Postnatal Development 2307916

Abstract

Abstract Introduction Inflammation in early life is an established risk factor for the diagnosis of neurodevelopmental disorders, highlighting the consequences of immune activation during neurodevelopment. While microglial involvement has been studied extensively, the contributions of other immune cells are poorly defined. Using Sprague Dawley rats, we identified a population of mast cells proximal to the hippocampal neurogenic niche (dentate gyrus), termed peri-hippocampal mast cells (phMCs). phMCs are highly proliferative, peak in number at postnatal day (PN) 7, steadily decline until PN14, and are no longer detected by the third week of life, a pattern reminiscent of a critical developmental window. This temporal profile coincides with the peak of hippocampal neurogenesis. Thus, we hypothesize that phMCs contribute to hippocampal neurogenesis through two complementary mechanisms: 1) the release of histamine that directly binds to neural precursor cells and 2) histamine-dependent induction of blood-brain barrier (BBB) permeability, permitting peripheral growth factors access to the neurogenic niche. Methods To test this, hippocampal neurogenesis and BBB permeability were evaluated following pharmacological phMC degranulation. BBB permeability was assessed by measuring leakage of peripherally injected tracers in brain homogenates. Results Degranulation at PN2 caused region-specific, histamine-dependent leakage of 70-kDa molecules into the hippocampus but not the cerebellum, whereas at PN7 leakage was restricted to molecules ≤10-kDa. phMC degranulation at PN5—7 significantly increased BrdU+ neurons in the dentate gyrus at PN14. Conclusion These findings indicate that phMCs have the functional capacity to promote hippocampal neurogenesis and regulate BBB permeability in a developmentally and regionally constrained manner. Early degranulation at PN2 permits large-molecule entry, whereas later degranulation induces limited, size-restricted permeability, consistent with BBB maturation. Funding Source 5R01MH052716-27 to MMM (PI); 3R01MH052716-28S1 to AWA (trainee) Topic Categories Neuroimmunology (NEUR)