Intercellular signaling molecules such as cytokines and their receptors enable immune cells to communicate with one another and their surrounding microenvironments. Emerging evidence suggests that the same signaling pathways that regulate inflammatory responses to injury and disease outside of the brain also play powerful roles in brain development, plasticity, and function. These observations raise the question of how the same signaling molecules can play such distinct roles in peripheral tissues compared to the central nervous system, a system previously thought to be largely protected from inflammatory signaling. Here, we review evidence that the specialized roles of immune signaling molecules such as cytokines in the brain are to a large extent shaped by neural activity, a key feature of the brain that reflects active communication between neurons at synapses. We discuss the known mechanisms through which microglia, the resident immune cells of the brain, respond to increases and decreases in activity by engaging classical inflammatory signaling cascades to assemble, remodel, and eliminate synapses across the lifespan. We integrate evidence from (1) in vivo imaging studies of microglia-neuron interactions, (2) developmental studies across multiple neural circuits, and (3) molecular studies of activity-dependent gene expression in microglia and neurons to highlight the specific roles of activity in defining immune pathway function in the brain. Given that the repurposing of signaling pathways across different tissues may be an important evolutionary strategy to overcome the limited size of the genome, understanding how cytokine function is established and maintained in the brain could lead to key insights into neurological health and disease.
Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes throughout life, but the functions of OPCs are not limited to oligodendrogenesis. Here we show that OPCs contribute to thalamocortical presynapse elimination in the developing and adult mouse visual cortex. OPC-mediated synapse engulfment increases in response to sensory experience during neural circuit refinement. Our data suggest that OPCs may regulate synaptic connectivity in the brain independently of oligodendrogenesis.
Oligodendrocyte precursor cells (OPCs) are a highly proliferative class of non-neuronal progenitors that largely give rise to myelinating oligodendrocytes. Although OPCs persist across the lifespan, their functions beyond oligodendrogenesis remain to be fully characterized. Here, we show that OPCs contribute to neural circuit remodeling by internalizing presynaptic thalamocortical inputs in both the developing and adult mouse visual cortex. Inputs internalized by OPCs localize to lysosomal compartments, consistent with OPC engulfment of synapses occurring through phagocytosis. We further show that engulfment by OPCs is heightened during experience-dependent plasticity, and that this experience-dependent increase in engulfment requires microglia. These data identify a new function for OPCs beyond the generation of oligodendrocytes and reveal that distinct non-neuronal populations collaborate to modulate synaptic connectivity.
Cytokine signaling between microglia and neurons is required for synapse elimination during brain development, but the mechanisms by which neurons respond to microglia-derived cytokines remain to be fully defined. Here, we demonstrate that microglia are necessary for sensory experience-dependent synapse elimination in the dorsal lateral geniculate nucleus (dLGN) of the mouse, a process previously shown to be mediated by the microglia-derived cytokine TWEAK and its neuronal receptor Fn14. Single-nucleus RNA-sequencing in mice lacking Fn14 or TWEAK at the height of experience-dependent refinement revealed that TWEAK-Fn14 signaling coordinates robust programs of gene expression in excitatory thalamocortical neurons of the dLGN. Gene targets of TWEAK and Fn14 are enriched for regulators of synapse and chromatin remodeling, suggesting that TWEAK-Fn14 signaling coordinates neuronal transcription to promote circuit refinement and epigenomic maturation in response to experience. We further find that Fn14 expression is not restricted to the dLGN but extends to other brain regions as well, both during development and in the adult. Consistent with the expression of Fn14 outside of the visual system, Fn14 knockout mice show significant impairments in multiple tests of memory task proficiency. At baseline, loss of Fn14 does not affect macroscopic neural activity measured by electroencephalogram recordings in vivo. However, mice lacking Fn14 displayed worse seizure outcomes and were less likely to survive when seizures were pharmacologically induced. Thus, TWEAK-Fn14 signaling coordinates neuronal transcription during development and contributes to cognitive function in the adult. Taken together, these data reveal that molecular pathways associated with inflammation in the periphery can coordinate with sensory experience to shape neural connectivity across the lifespan.
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