Journal
CELL
Volume 185, Issue 18, Pages 3390-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2022.07.026
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Funding
- Howard Hughes Medical Institute
- Foundation for Medical Research (FRM, France)
- ANR [ANR-11-BSV4-008, ANR-17-CE16-0010-01]
- NIH BRAIN Initiative [1U01NS103558]
- French Ministry of Research and Education
- NIH [5T32HL110852-05]
- ANID-Millennium Science Initiative Program [NCN19_168]
- Philomathia Foundation and Chan Zuckerberg Initiative Imaging Scientist program
- National Institute of General Medical Sciences Maximizing Investigators' Research [GM130386]
- National Institutes of Health [R01 GM075252]
- Biogen Sponsored Research Agreement
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This study discovers the existence of synapses between axons and primary cilia and reveals their role in neuronal communication. The cilia are enriched in serotonin receptors and can be stimulated by serotonin released from axons, altering the epigenetic state of the postsynaptic neuron.
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(alpha q/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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