The cytokine receptor Fn14 regulates neuronal transcription during development and brain function in the adult

Abstract

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 neuronal transcription and connectivity across the lifespan. Highlights Microglia regulate sensory-dependent refinement at the retinogeniculate synapse TWEAK-Fn14 signaling induces the expression of neuronal genes involved in synaptic and chromatin remodeling Fn14 signaling is dispensable for learning but required for memory in multiple tasks Loss of Fn14 exacerbates seizure susceptibility and the severity of seizure outcomes