Neuronal UBE3A loss engages a TNF-driven neuron-to-microglia axis that promotes synapse remodeling.

Neuron-microglia communication shapes neuroimmune homeostasis and circuit maturation, yet the neuron-derived cues that tune microglial inflammatory state and phagocytic programs remain incompletely defined. The E3 ubiquitin ligase UBE3A is critical for brain development and synaptic function, and altered UBE3A dosage or activity is linked to neurodevelopmental phenotypes with emerging connections to inflammation. Using Angelman syndrome (AS), where UBE3A loss is largely neuron-selective due to imprinting, as a tractable framework, we investigated how neuronal UBE3A deficiency engages microglial programs. In human iPSC-derived neuron-microglia co-cultures, neuronal UBE3A depletion induced a TNF-associated secretory signature and was accompanied by increased microglial inflammatory markers, including complement components. Neuron-conditioned media was sufficient to elicit microglial cytokine/complement transcripts, supporting a role for soluble neuron-derived cues. In these co-cultures, neuronal UBE3A loss increased synapse engulfment by microglia, which was reduced by TNF receptor pathway inhibition with the TNFR1 antagonist R7050 alongside decreased microglial inflammatory readouts. In vivo, juvenile AS mouse hippocampus showed early microglial dysregulation, and reanalysis of a maternal-deletion AS pig single-nucleus RNA-seq dataset revealed enrichment of microglial activation and phagosome/lysosome pathways. Together, these findings implicate a TNF-linked neuron-to-microglia signaling axis downstream of neuronal UBE3A loss that can be pharmacologically modulated during development.