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Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered a new kind of synapse. The “axo-ciliary” synapse is between axons and the primary cilia of target neurons. Mediated by serotonin released from axonal varicosities and the cilia-restricted serotonin receptor 5-hydroxytryptamine receptor 6 (gene: HTR6, protein: 5-HT6), activation of axo-ciliary synapses drives a RhoA-mediated signaling cascade that modifies nuclear actin to acetylate histones and increase chromatin accessibility. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron’s epigenetic state.