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

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 discov...

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Published inCell Vol. 185; no. 18; pp. 3390 - 3407.e18
Main Authors Sheu, Shu-Hsien, Upadhyayula, Srigokul, Dupuy, Vincent, Pang, Song, Deng, Fei, Wan, Jinxia, Walpita, Deepika, Pasolli, H Amalia, Houser, Justin, Sanchez-Martinez, Silvia, Brauchi, Sebastian E, Banala, Sambashiva, Freeman, Melanie, Xu, C Shan, Kirchhausen, Tom, Hess, Harald F, Lavis, Luke, Li, Yulong, Chaumont-Dubel, Séverine, Clapham, David E
Format Journal Article
LanguageEnglish
Published United States Elsevier 01.09.2022
Subjects
Axons - physiology
Cell Nucleus - metabolism
Chromatin - chemistry
Chromatin - metabolism
Cilia - metabolism
Hippocampus - cytology
Hippocampus - physiology
Life Sciences
Neurobiology
Neurons and Cognition
Serotonin - metabolism
Signal Transduction
Synapses - physiology
FIB-SEM
serotonin
fluorescence lifetime imaging
histone modification
primary cilia
chromatin accessibility
pyramidal neurons
GPCR signaling
nuclear actin
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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 -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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Conceptualization, S.-H.S. and D.E.C.; methodology, S.-H.S., S.E.B., S.B., C.S.X., F.D., J.W., Y.L., D.W., S.S.-M., J.H., and T.K.; investigation, S.-H.S., S.U., V.D., S.E.B., S.B., F.D., J.W., Y.L., M.F., H.A.P., S.P., C.S.X., and T.K.; writing–original draft, S.-H.S.; writing–review and editing, S.-H.S., F.D., J.W., L.L., S.E.B., S.C.-D., and D.E.C.; funding acquisition, S.-H.S., L.L., S.C.-D., T.K., and D.E.C.; resources, H.F.H.; visualization, S.-H.S., S.U., F.D., and J.W.; supervision, S.-H.S. and D.E.C.
AUTHOR CONTRIBUTIONS
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2022.07.026