There is ample evidence of immune dysfunction in neurodevelopmental and psychiatric disorders and immune signaling is known to impact synapse development. Microglia, the tissue-resident macrophages of the brain, are key conduits of these immune signals. They can both promote synapse formation and prune away synapses, which has been shown to be regulated by immune molecules in physiologic development. However, the discovery of many other immune cells in the meningeal compartment surrounding the brain at rest raises the question of whether these cells play a physiologic role in the central nervous system, perhaps via communication with microglia. Lymphocytes and lymphocyte-derived cytokines have been shown to promote normal cognition and behavior in adult mice, but their physiological roles, particularly during development, are largely unknown. Our group identified abundant lymphocytes in the brain meninges throughout postnatal development. We also find that microglia are competent to respond to lymphocyte-derived cytokines, particularly Interleukin-13 (IL-13), a canonical type 2 cytokine. IL-13 induces transcription of genes in microglia consistent with cell migration, and cell-cell and extracellular matrix (ECM) adhesion, which may increase their synapse remodeling functions. The predominant producers of IL-13 under homeostatic conditions are type 2 innate lymphoid cells (ILC2s), which we find present in the developing meninges and poised for cytokine production during a critical period of synapse formation and pruning. Loss of ILC2s leads to altered inhibitory and excitatory synapse numbers in the developing cortex. Based on these data, the central hypothesis of this work is that ILC2s promote post-natal synapse development via IL-13 signaling to microglia and regulation of their synaptic remodeling functions. To test this hypothesis, this proposal will determine the requirement for ILC2s and IL-13 in promoting cortical synapse function (Aim 1) and define the direct impact of IL-13 signaling on microglia synapse remodeling function, namely engulfment (Aim 2). Genetic mouse models will be used for targeted deletion of ILC2s and of the IL-13 receptor from microglia. This work will employ slice electrophysiology to determine synaptic function as well as immunohistochemistry and high-resolution imaging to examine microglial engulfment and synapse density. This work leverages the expertise and tools of neurodevelopmental glial biologists and innate immunologists to address this important question in neuroimmunology. Successful completion of these aims will reveal a novel role for ILC2-microglia communication in regulating neurodevelopment. Elucidating the impact of lymphocytes and their cytokines on physiologic brain development is significant for understanding how dysregulated immune responses may contribute to neurodevelopmental disorders.
Defining the physiologic role of immune signaling in neurodevelopment is significant to understanding potential dysregulation of synapse homeostasis in developmental disorders and psychiatric diseases. However, little is known about the role of immune cells called lymphocytes in brain development, despite their normal presence in the meningeal membranes surrounding the brain. This work will investigate how lymphocytes communicate to the brain to help form proper synaptic connections and will increase our understanding of how developmental processes may be affected in disease.
