The goal of this proposal is to determine how microglia and sensory experience integrate to remodel synapses into precise, functional brain maps. Trillions of synapses form highly precise topographic maps in the brain representing each part of the body. These maps are shaped and maintained by sensory experience (vision, touch, etc.), including elimination of less active synapses and formation and maintenance of other synapses. Despite over 50 years of research, the underlying mechanisms by which experience dictates removal or maintenance of specific synapses still remains an open question. We made the initial exciting and unexpected observation that microglia, the resident CNS macrophages, engulfed and eliminated a subset of less active synapses in the developing retinogeniculate system. Further, reducing microglia-mediated engulfment of synapses by 50% (complement receptor 3 KO) resulted in sustained increases in retinogeniculate synapse number. This work established a new way of thinking about synaptic remodeling and inspired several important new questions: Is microglia-mediated synaptic remodeling necessary for achieving functional circuits? Do microglia remodel synapses in the adult brain? How does neural activity regulate microglia-mediated synaptic remodeling? The retinogeniculate system was limiting for addressing these questions. We required a robust system for studying synaptic remodeling that involved plasticity of synapses throughout life, tractable assays for measuring function, and a topographic arrangment with high spatial and temporal resolution. The mouse barrel cortex fit all these critera and will enable us to test the hypothesis that experience regulates microglia to shape developing and mature syanpses into functional brain circuits. Our new preliminary data show for the first time that microglia engulf excitatory thalamocortical (TC) synapses in the developing barrel cortex and following sensory deprivation (whisker removal) in the neonate. Further, mice deficient in microglia (colony stimulating factor 1 receptor KO; CSF1R KO) have defects in the development of approriate barrel architecture and TC input elimination following whisker deprivation is completely blocked in mice deficient in a microglia-specific chemokine receptor (fractalkine receptor KO, CX3CR1 KO). We will now use a combination of high resolution static and functional imaging and molecular biology in the mouse barrel cortex to: 1) Determine whether microglia sculpt developing cortical circuits into functional brain maps (Aim 1). 2) Determine whether microglia regulate experience-dependent plasticity of cortical maps in the neonate and adult (Aim 2). 3) Identify how microglia remodel synapses in response to changes in neural activity (Aim 3). Answers will uncover new mechanisms regulating how sensory experience regulates the development of structural and functional brain maps, will identify new ways to achieve plasticity in the adult brain, and will provide new mechanistic insight into how synapses remodel in multiple contexts (development, learning and memory, disease, etc.).
Defects in sensory processing, microglial reactivity, and synapses are now considered hallmark features of many neurological disorders from autism to Alzheimer?s disease. However, it is unclear how cellular changes manifest into devastating symptoms in patients. The current proposal will shed new light on how sensory experience regulates microglia to remodel neural circuits in the healthy developing and adult brain with a long- term goal of applying these mechanisms to uncover novel etiologies for neuropsychiatric disorders such as autism and schizophrenia with underlying defects in microglia and synaptic connectivity.
|Werneburg, Sebastian; Feinberg, Philip A; Johnson, Kasey M et al. (2017) A microglia-cytokine axis to modulate synaptic connectivity and function. Curr Opin Neurobiol 47:138-145|