Project description:Synapse formation and elimination are two crucial processes that concurrently take place in the developing brain. Astrocytes and microglia have been shown to control both processes. However, it is largely unknown how these two major glial cell types of the central nervous system (CNS) communicate to balance synapse formation and elimination. Astrocytes secrete a synaptogenic protein called Hevin/SPARCL1, which induces the formation and plasticity of thalamocortical synapses in the mouse visual cortex. Hevin does so by physically localizing to synaptic clefts and bridging the thalamic axon/cortical dendrite via its interactions with presynaptic Neurexin1a and postsynaptic Neuroligin1b. Here, we found that in addition to this synaptogenic function, Hevin directly signals to microglia cells by interacting with Toll-like Receptors (TLRs) TLR4 and TLR2. This signaling occurs when Hevin is proteolytically cleaved producing an active C-terminal fragment. This fragment is sufficient to upregulate TLR2 expression in microglia and increase microglia phagocytic activity in vivo. This signaling is required for proper refinement of thalamocortical synapses in early postnatal development and for early life ocular dominance plasticity.
Project description:Microglia were FACS-isolated from developing mouse corpus callosum at postnatal days 0, 7, and 21, then sequenced by 10X Genomics single-cell sequencing.
Project description:This study defines a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus.
Project description:Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the mouse medial prefrontal cortex (mPFC). Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.