IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36872-8.html
   My bibliography  Save this article

A combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop

Author

Listed:
  • Justin H. Trotter

    (Stanford University School of Medicine)

  • Cosmos Yuqi Wang

    (Stanford University School of Medicine)

  • Peng Zhou

    (Stanford University School of Medicine)

  • George Nakahara

    (Stanford University School of Medicine)

  • Thomas C. Südhof

    (Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

Disrupted synaptic inhibition is implicated in neuropsychiatric disorders, yet the molecular mechanisms that shape and sustain inhibitory synapses are poorly understood. Here, we show through rescue experiments performed using Neurexin-3 conditional knockout mice that alternative splicing at SS2 and SS4 regulates the release probability, but not the number, of inhibitory synapses in the olfactory bulb and prefrontal cortex independent of sex. Neurexin-3 splice variants that mediate Neurexin-3 binding to dystroglycan enable inhibitory synapse function, whereas splice variants that don’t allow dystroglycan binding do not. Furthermore, a minimal Neurexin-3 protein that binds to dystroglycan fully sustains inhibitory synaptic function, indicating that trans-synaptic dystroglycan binding is necessary and sufficient for Neurexin-3 function in inhibitory synaptic transmission. Thus, Neurexin-3 enables a normal release probability at inhibitory synapses via a trans-synaptic feedback signaling loop consisting of presynaptic Neurexin-3 and postsynaptic dystroglycan.

Suggested Citation

  • Justin H. Trotter & Cosmos Yuqi Wang & Peng Zhou & George Nakahara & Thomas C. Südhof, 2023. "A combinatorial code of neurexin-3 alternative splicing controls inhibitory synapses via a trans-synaptic dystroglycan signaling loop," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36872-8
    DOI: 10.1038/s41467-023-36872-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36872-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-36872-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Ed S. Lein & Michael J. Hawrylycz & Nancy Ao & Mikael Ayres & Amy Bensinger & Amy Bernard & Andrew F. Boe & Mark S. Boguski & Kevin S. Brockway & Emi J. Byrnes & Lin Chen & Li Chen & Tsuey-Ming Chen &, 2007. "Genome-wide atlas of gene expression in the adult mouse brain," Nature, Nature, vol. 445(7124), pages 168-176, January.
    2. Markus Missler & Weiqi Zhang & Astrid Rohlmann & Gunnar Kattenstroth & Robert E. Hammer & Kurt Gottmann & Thomas C. Südhof, 2003. "α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis," Nature, Nature, vol. 423(6943), pages 939-948, June.
    3. Jinye Dai & Christopher Patzke & Kif Liakath-Ali & Erica Seigneur & Thomas C. Südhof, 2021. "GluD1 is a signal transduction device disguised as an ionotropic receptor," Nature, Nature, vol. 595(7866), pages 261-265, July.
    4. Fujun Luo & Alessandra Sclip & Sean Merrill & Thomas C. Südhof, 2021. "Neurexins regulate presynaptic GABAB-receptors at central synapses," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Brian A Lloyd & Ying Han & Rebecca Roth & Bo Zhang & Jason Aoto, 2023. "Neurexin-3 subsynaptic densities are spatially distinct from Neurexin-1 and essential for excitatory synapse nanoscale organization in the hippocampus," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. S. Vickovic & B. Lötstedt & J. Klughammer & S. Mages & Å Segerstolpe & O. Rozenblatt-Rosen & A. Regev, 2022. "SM-Omics is an automated platform for high-throughput spatial multi-omics," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Léa J. Becker & Clémentine Fillinger & Robin Waegaert & Sarah H. Journée & Pierre Hener & Beyza Ayazgok & Muris Humo & Meltem Karatas & Maxime Thouaye & Mithil Gaikwad & Laetitia Degiorgis & Marie des, 2023. "The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    3. Tingting Bo & Jie Li & Ganlu Hu & Ge Zhang & Wei Wang & Qian Lv & Shaoling Zhao & Junjie Ma & Meng Qin & Xiaohui Yao & Meiyun Wang & Guang-Zhong Wang & Zheng Wang, 2023. "Brain-wide and cell-specific transcriptomic insights into MRI-derived cortical morphology in macaque monkeys," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. E. R. Velasco & A. Florido & Á Flores & E. Senabre & A. Gomez-Gomez & A. Torres & A. Roca & S. Norrholm & E. L. Newman & P. Das & R. A. Ross & A. Lori & O. J. Pozo & K. J. Ressler & L. L. Garcia-Estev, 2022. "PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Vincent Bazinet & Justine Y. Hansen & Reinder Vos de Wael & Boris C. Bernhardt & Martijn P. Heuvel & Bratislav Misic, 2023. "Assortative mixing in micro-architecturally annotated brain connectomes," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Xiaomeng Wan & Jiashun Xiao & Sindy Sing Ting Tam & Mingxuan Cai & Ryohichi Sugimura & Yang Wang & Xiang Wan & Zhixiang Lin & Angela Ruohao Wu & Can Yang, 2023. "Integrating spatial and single-cell transcriptomics data using deep generative models with SpatialScope," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    7. Maxime Brunner & David Lopez-Rodriguez & Judith Estrada-Meza & Rafik Dali & Antoine Rohrbach & Tamara Deglise & Andrea Messina & Bernard Thorens & Federico Santoni & Fanny Langlet, 2024. "Fasting induces metabolic switches and spatial redistributions of lipid processing and neuronal interactions in tanycytes," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    8. Harry Carey & Michael Pegios & Lewis Martin & Chris Saleeba & Anita J. Turner & Nicholas A. Everett & Ingvild E. Bjerke & Maja A. Puchades & Jan G. Bjaalie & Simon McMullan, 2023. "DeepSlice: rapid fully automatic registration of mouse brain imaging to a volumetric atlas," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    9. Manvendra Singh & Ying Zhao & Vinicius Daguano Gastaldi & Sonja M. Wojcik & Yasmina Curto & Riki Kawaguchi & Ricardo M. Merino & Laura Fernandez Garcia-Agudo & Holger Taschenberger & Nils Brose & Dani, 2023. "Erythropoietin re-wires cognition-associated transcriptional networks," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Qiang Liu & Benjamin J. Bell & Dong Won Kim & Sang Soo Lee & Mehmet F. Keles & Qili Liu & Ian D. Blum & Annette A. Wang & Elijah J. Blank & Jiali Xiong & Joseph L. Bedont & Anna J. Chang & Habon Issa , 2023. "A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    11. Rongbo Shen & Lin Liu & Zihan Wu & Ying Zhang & Zhiyuan Yuan & Junfu Guo & Fan Yang & Chao Zhang & Bichao Chen & Wanwan Feng & Chao Liu & Jing Guo & Guozhen Fan & Yong Zhang & Yuxiang Li & Xun Xu & Ji, 2022. "Spatial-ID: a cell typing method for spatially resolved transcriptomics via transfer learning and spatial embedding," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    12. Xosé Luís Deán-Ben & Justine Robin & Daniil Nozdriukhin & Ruiqing Ni & Jim Zhao & Chaim Glück & Jeanne Droux & Juan Sendón-Lago & Zhenyue Chen & Quanyu Zhou & Bruno Weber & Susanne Wegener & Anxo Vida, 2023. "Deep optoacoustic localization microangiography of ischemic stroke in mice," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    13. Riccardo De Santis & Fred Etoc & Edwin A. Rosado-Olivieri & Ali H. Brivanlou, 2021. "Self-organization of human dorsal-ventral forebrain structures by light induced SHH," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    14. Dongsheng Xiao & Brandon J. Forys & Matthieu P. Vanni & Timothy H. Murphy, 2021. "MesoNet allows automated scaling and segmentation of mouse mesoscale cortical maps using machine learning," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    15. P. Bielefeld & A. Martirosyan & S. Martín-Suárez & A. Apresyan & G. F. Meerhoff & F. Pestana & S. Poovathingal & N. Reijner & W. Koning & R. A. Clement & I. Veen & E. M. Toledo & O. Polzer & I. Durá &, 2024. "Traumatic brain injury promotes neurogenesis at the cost of astrogliogenesis in the adult hippocampus of male mice," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    16. Duy Pham & Xiao Tan & Brad Balderson & Jun Xu & Laura F. Grice & Sohye Yoon & Emily F. Willis & Minh Tran & Pui Yeng Lam & Arti Raghubar & Priyakshi Kalita-de Croft & Sunil Lakhani & Jana Vukovic & Ma, 2023. "Robust mapping of spatiotemporal trajectories and cell–cell interactions in healthy and diseased tissues," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    17. Andrew Jones & Diana Cai & Didong Li & Barbara E. Engelhardt, 2024. "Optimizing the design of spatial genomic studies," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    18. David Wolf & Renée Hartig & Yi Zhuo & Max F. Scheller & Mirko Articus & Marcel Moor & Valery Grinevich & Christiane Linster & Eleonora Russo & Wolfgang Weber-Fahr & Jonathan R. Reinwald & Wolfgang Kel, 2024. "Oxytocin induces the formation of distinctive cortical representations and cognitions biased toward familiar mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    19. Ayelet M. Rosenberg & Manish Saggar & Anna S. Monzel & Jack Devine & Peter Rogu & Aaron Limoges & Alex Junker & Carmen Sandi & Eugene V. Mosharov & Dani Dumitriu & Christoph Anacker & Martin Picard, 2023. "Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    20. Deepanjali Dwivedi & Dimitri Dumontier & Mia Sherer & Sherry Lin & Andrea M. C. Mirow & Yanjie Qiu & Qing Xu & Samuel A. Liebman & Djeckby Joseph & Sandeep R. Datta & Gord Fishell & Gabrielle Pouchelo, 2024. "Metabotropic signaling within somatostatin interneurons controls transient thalamocortical inputs during development," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36872-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.