Identification of microglia-specific molecules that dictate microglial responses to neural activity and function at developing and refining neural circuits

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Microglia, a relatively understudied resident CNS immune cell population, have for decades been regarded as functionally quiescent in the healthy brain parenchyma. However, recently, microglia were shown to dynamically modulate the motility of their fine processes, increase the contact frequency with less active synapses and ultimately prune these synapses by phagocytic engulfment in response to alterations in neural activity. These intriguing findings first indicated important physiological functions of microglia for the formation and refinement of neural circuits in the developing brain. However, the molecular mechanisms and functional consequences underlying these responses are completely unknown and mechanisms underlying activity-dependent synapse remodeling, in general, remain poorly defined. This proposal describes a multi-dimensional approach combining in vitro and in vivo models to unravel the molecular mechanisms of microglia-dependent synaptic plasticity and to assess the structural and functional consequences on the development and refinement of neural circuits in the healthy brain. One main element of our studies will be the ablation of microglia-specific genes implicated in cell motility, cytoskeletal rearrangements and phagocytic engulfment and the assessment of how these molecules regulate microglial functions in response to neural activity. Microglia-specific genes of interest (GOIs) that are regulated by neural activity will initially be identified by comparative transcriptional profiling of microglia either derived from mice housed under control conditions in a normal light/dark cycle, or from mice reared in the dark to dampen neural activity in the primary visual cortex area V1. Alternatively, public accessible gene expression profiles from close ontogenetic relatives, such as tissue-resident macrophages outside the brain, will be used to identify genes that are specifically regulated by neural activity. Furthermore, we will assess how genetic ablation of microglia and deletion of microglia-specific GOIs affect the development and refinement of structural and functional neural circuits in general. The proposed study will be the first to define microglia-specific genes that are regulated by neural activity and will develop and advance new technologies to genetically manipulate microglia. Moreover, these experiments will identify exciting new microglial targets that dictate synapse remodeling, and thereby control the development and refinement of structural and functional neural circuits in multiple contexts, including development and disease.