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A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility

Shu-Hsien Sheu,Srigokul Upadhyayula,Vincent Dupuy,Song Pang,Fei Deng,Jinxia Wan,Deepika Walpita,H. Amalia Pasolli,Justin Houser,Silvia Sanchez-Martinez,Sebastian E. Brauchi,Sambashiva Banala,Melanie Freeman,C. Shan Xu,Tom Kirchhausen,Harald F. Hess,Luke Lavis,Yulong Li,Séverine Chaumont-Dubel,David E. Clapham

Summary Chemical synapses between axons and dendrites mediate neuronal intercellular communication. Here, we describe a synapse between axons and primary cilia: the axo-ciliary synapse. Using enhanced focused ion beam-scanning electron microscopy on samples with optimally preserved ultrastructure, we discovered synapses between brainstem serotonergic axons and the primary cilia of hippocampal CA1 pyramidal neurons. Functionally, these cilia are enriched in a ciliary-restricted serotonin receptor, the 5-hydroxytryptamine receptor 6 (5-HTR6). Using a cilia-targeted serotonin sensor, we show that opto- and chemogenetic stimulation of serotonergic axons releases serotonin onto cilia. Ciliary 5-HTR6 stimulation activates a non-canonical G αq/11 -RhoA pathway, which modulates nuclear actin and increases histone acetylation and chromatin accessibility. Ablation of this pathway reduces chromatin accessibility in CA1 pyramidal neurons. As a signaling apparatus with proximity to the nucleus, axo-ciliary synapses short circuit neurotransmission to alter the postsynaptic neuron’s epigenetic state.