Project 3: Microglia heterogeneity and function in interneuron development

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Abstract Neural circuits require precise placement of correct numbers of interneurons (INs). This delicate process is derailed in neurodevelopmental and neuropsychiatric disease. Microglia, the brain resident macrophages, influence many aspects of brain development, including genesis, migration and maturation of cortical interneurons (cINs). In our preliminary study leading up to this proposal, we discovered diverse molecular and cellular properties of human microglia in the developing forebrain and we found that specific molecularly- defined subtypes are differentially distributed across brain regions. Furthermore, our results show that GPR56 expression defines a subset of human microglia and that deletion of murine microglial Gpr56 leads to a significant reduction in the numbers of PV+ interneurons in specific brain region. However, the full scope of microglia transcriptomic and functional heterogeneity, especially in the human brain, remains elusive. The proposed research will establish the postnatal cellular and molecular heterogeneity of microglia in the human caudal and medial ganglionic eminence with a specific focus on GPR56 in microglia. We hypothesize that microglial GPR56 promotes interneuron development. To test this and corollary hypotheses, we will carry out the following three aims: (1) Define microglia morphology, distribution, and their interactions with neural progenitors (NPCs) and young neurons in the human GEs and the Arc (a unique cluster of migratory interneurons found at birth in the vicinity of the human lateral ventricles); (2) Characterize microglial transcriptomic heterogeneity in the developing hMGE, hCGE and the Arc; and (3) Investigate the cell-type- specific function of microglial GPR56 in interneuron development using microglia-specific conditional knockout mouse model. Most meaningfully, we are conducting our studies using both human brain tissues and transgenic mouse models, to take advantage of the many manipulations that can be done in mice, but always grounding our work in the human conditions we seek to understand. The success of the proposed research will open a novel and important line of research into the origin of neurodevelopmental disorders, such as autism and schizophrenia. Given the status of aGPCRs as drug targets, this line of research carries tremendous translational potential. In particular, it is feasible to begin designing drugs that modify the action of GPR56 given the discovery of its crystal structure.