Neuron-Microglia Crosstalk in Development: A new role for the neuron-derived cytokine IL34 in microglial function

工作总结

SUMMARY OF WORK Microglia-neuron crosstalk in development is critical for the formation and refinement of synaptic connections. In this project, I propose to investigate a novel role for the neuron-derived cytokine IL34 in controlling the function of microglia to close critical periods of synaptic plasticity in development. IL34, along with the canonical ligand CSF1, signals through the CSF1 receptor on microglia to promote differentiation. Previous work suggests that embryonic and neonatal microglia depend primarily on CSF1 from other glia, while adult microglia in regions such as the cortex and striatum depend on IL34 from neurons. I have shown that IL34 expression increases between postnatal day 8 (P8) and P15 in the anterior cingulate cortex. Interestingly, this window corresponds with peak synapse engulfment in the ACC, suggesting that IL34 may play a role in dictating microglial function rather than just survival. Furthermore, my preliminary data demonstrate that microglia in mice lacking functional IL34LacZ/LacZ show an elevated inflammatory profile and do not upregulate microglial “maturity” marker TMEM119 between P8 and P15. The overarching goal of this proposal is to test the hypothesis that IL34 is a neuronal activity-dependent signal that influences microglia function to close critical periods of developmental plasticity. In Aim 1 I will investigate how chemogenetic activation or inhibition of neuronal activity in development controls IL34 gene and protein expression in all neuron subtypes. In Aim 2, I will determine whether transiently blocking IL34 or CSF1 impacts microglial pruning of thalamocortical synapses in the ACC, and if this has an effect of communicative behaviors (USVs). These studies will elucidate the mechanistic implications of differential CSF1R signaling in the brain during development, and the functional consequences for microglial.