Microglia-Astrocyte Crosstalk Regulating SynapseRemodeling

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Project Summary The goal of this proposal is to determine how microglia and astrocytes communicate to remodel synapses. Trillions of synapses form highly precise circuit maps in the brain. These maps are shaped and maintained by sensory experience (vision, touch, etc.), including elimination of less active synapses and f maintenance and strengthening of other synapses. Despite over 50 years of research, the underlying mechanisms by which activity dictates removal of some synapses, but not others, remains an open question. We made the initial discovery that microglia, a resident central nervous system (CNS) macrophage, engulf and eliminate less active synapses in the developing retinogeniculate and barrel cortex circuits. In the last funding cycle, we showed that removal of whiskers on one side of the snout in neonates resulted in microglial engulfment and elimination of thalamocortical (TC) synapses in the corresponding barrel cortex. Unlike the retinogeniculate circuit, this was not regulated by complement. Instead, microglia failed to engulf and eliminate TC synapses in mice deficient in neuronal fractalkine (CX3CL1)-to microglial fractalkine receptor (CX3CR1) signaling. This work established that diverse glial mechanisms regulate activity-dependent synapse remodeling and opened up new questions: Do microglia remodel synapses in the adult brain? With evidence that astrocytes also engulf synapses in other CNS circuits, are astrocytes also involved in barrel cortex synapse remodeling? If so, do they communicate with microglia to regulate this process? Our new preliminary data show that astrocytes do not engulf synapses in response to whisker removal in neonates, but rather they reduce their contact with synapses in a CX3CL1-dependent manner. Also, microglia no longer engulf TC synapses following whisker removal in older animals, concomitant with elevated astrocyte synapse ensheathment. Cell-specific RNAseq following whisker removal further reveals canonical Wnt signaling as a putative mechanism by which microglia signal to astrocytes to regulate synapse ensheathment. We now propose a novel model by which microglia regulate astrocyte ensheathment of synapses in an activity and CX3CL1-CX3CR1-Wnt dependent manner. In turn, microglia gain access to engulf and remove TC synapses. We will now leverage the power of the barrel cortex circuit with cell-specific genetic approaches to: 1) Define the developmental window for CX3CL1-CX3CR1- dependent microglial synapse engulfment and astrocyte synapse ensheathment (Aim 1). 2) Determine if astrocyte ensheathment of synapses impacts microglia-dependent synapse remodeling (Aim 2). 3) Identify how microglia regulate astrocyte ensheathment of synapses (Aim 3). Answers will address how some synapses are eliminated by glia while others are left intact—a key open question in the field with implications for a variety of neurodevelopmental disorders and neurodegenerative diseases with underlying changes in synaptic connectivity.