Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

Abstract

Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remains a key open question. Here, whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. We show that this synapse elimination is dependent on the microglial fractalkine receptor, CX3CR1, but not complement receptor 3, signaling. Further, mice deficient in the CX3CR1 ligand (CX3CL1) also have profound defects in synapse elimination. Single-cell RNAseq then revealed that Cx3cl1 is cortical neuron-derived and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and microglia following whisker lesioning.Finally, inhibition of ADAM10 phenocopies Cx3cr1 -/and Cx3cl1 -/synapse elimination defects.Together, these results identify novel neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain. 3

Axonal chemokine-like Orion induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling

“…2c). Fractalkine and its receptor, CX 3 CR1, have been recently shown to be required for post-trauma cortical brain neuron microgliamediated remodeling in a mouse whisker lesioning paradigm 21 . We observed that the change of the CX 3 C motif into CX 4 C or AX 3 C blocked the Orion function necessary for the MB pruning ( Supplementary Fig.…”

The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development

“…However, later studies in the cortex using sensory lesion models have given conflicting results. A study using the whisker-trimming model in CR3-deficient mice found that CR3 is dispensable for lesion-induced loss of thalamocortical inputs to the SS cortex in P4-P10 mice, whereas CX3CL1-CX3CR1 signaling is required 48 . Another study examining ocular dominance plasticity (ODP) in V1 cortex of C1q knockout mice showed that basal development of spines on L2/3 neurons were unchanged from P10-P30, and C1q is dispensable for ODP 49 .…”

Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia

“…Why specific neuronal structures are targeted, given that these complement factors represent secreted soluble proteins, remains unclear. Complement‐independent microglial synaptic elimination has also been demonstrated in other regions, including the hippocampus (Paolicelli et al , ; Weinhard et al , ) and barrel cortex (Gunner et al , ). Finally, in the dLGN, astrocytes also contribute to developmental pruning through TAM receptor‐specific mechanisms (Chung et al , ).…”