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Updated: Aug 30, 2025

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
A serotonergic axon-cilium synapse drives nuclear signaling to alter chromatin accessibility
Shu-Hsien Sheu1, Srigokul Upadhyayula2, Vincent Dupuy3
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA; Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Department of Pathology, Boston, MA, USA; Howard Huges Medical Institute, Boston Children's Hospital, Department of Cardiology, Boston, MA, USA.
Abstract:
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 Gαq/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.
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