{"_id":"17280","volume":10,"pmid":1,"status":"public","type":"journal_article","month":"07","has_accepted_license":"1","oa_version":"Published Version","scopus_import":"1","publication":"Science Advances","acknowledgement":"Ajap1HA/HA and Ajap1W183C/+ mice were generated in collaboration with Pawel Pelczar at the center for transgenic models at the University of Basel, Switzerland. We thank the imaging core facility (IMCF, University of Basel) and in particular A. Ferrand for the technical assistance provided on the OMX 3D-SIM microscope.\r\nThis work was supported by a grant from the Swiss National Science Foundation (SNF) to B.B. (31003A-152970, 310030B-201291), an NIH grant to E.A. and E.H.S. (R01NS058721), DFG grants to B.F. (TRR 152 project ID 239283807, FA 332/15-1, 16-1), and grants to P.S. from AIMS-2-TRIALS, which are supported by the Innovative Medicines Initiatives from the European Commission joint undertaking under grant agreement No 777394.","date_updated":"2024-07-22T06:32:51Z","article_type":"original","title":"Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release","day":"12","issue":"28","author":[{"full_name":"Früh, Simon","first_name":"Simon","last_name":"Früh"},{"full_name":"Boudkkazi, Sami","first_name":"Sami","last_name":"Boudkkazi"},{"full_name":"Koppensteiner, Peter","orcid":"0000-0002-3509-1948","id":"3B8B25A8-F248-11E8-B48F-1D18A9856A87","first_name":"Peter","last_name":"Koppensteiner"},{"first_name":"Vita","last_name":"Sereikaite","full_name":"Sereikaite, Vita"},{"first_name":"Li Yuan","last_name":"Chen","full_name":"Chen, Li Yuan"},{"full_name":"Fernandez-Fernandez, Diego","first_name":"Diego","last_name":"Fernandez-Fernandez"},{"first_name":"Pascal D.","last_name":"Rem","full_name":"Rem, Pascal D."},{"last_name":"Ulrich","first_name":"Daniel","full_name":"Ulrich, Daniel"},{"first_name":"Jochen","last_name":"Schwenk","full_name":"Schwenk, Jochen"},{"first_name":"Ziyang","last_name":"Chen","full_name":"Chen, Ziyang"},{"last_name":"Monnier","first_name":"Elodie Le","full_name":"Monnier, Elodie Le"},{"full_name":"Fritzius, Thorsten","first_name":"Thorsten","last_name":"Fritzius"},{"full_name":"Innocenti, Sabrina M.","first_name":"Sabrina M.","last_name":"Innocenti"},{"full_name":"Besseyrias, Valérie","first_name":"Valérie","last_name":"Besseyrias"},{"full_name":"Trovò, Luca","first_name":"Luca","last_name":"Trovò"},{"full_name":"Stawarski, Michal","first_name":"Michal","last_name":"Stawarski"},{"full_name":"Argilli, Emanuela","first_name":"Emanuela","last_name":"Argilli"},{"last_name":"Sherr","first_name":"Elliott H.","full_name":"Sherr, Elliott H."},{"last_name":"Van Bon","first_name":"Bregje","full_name":"Van Bon, Bregje"},{"full_name":"Kamsteeg, Erik Jan","first_name":"Erik Jan","last_name":"Kamsteeg"},{"full_name":"Iascone, Maria","first_name":"Maria","last_name":"Iascone"},{"full_name":"Pilotta, Alba","first_name":"Alba","last_name":"Pilotta"},{"last_name":"Cutrì","first_name":"Maria R.","full_name":"Cutrì, Maria R."},{"full_name":"Azamian, Mahshid S.","last_name":"Azamian","first_name":"Mahshid S."},{"full_name":"Hernández-García, Andrés","first_name":"Andrés","last_name":"Hernández-García"},{"last_name":"Lalani","first_name":"Seema R.","full_name":"Lalani, Seema R."},{"full_name":"Rosenfeld, Jill A.","first_name":"Jill A.","last_name":"Rosenfeld"},{"first_name":"Xiaonan","last_name":"Zhao","full_name":"Zhao, Xiaonan"},{"first_name":"Tiphanie P.","last_name":"Vogel","full_name":"Vogel, Tiphanie P."},{"first_name":"Herda","last_name":"Ona","full_name":"Ona, Herda"},{"first_name":"Daryl A.","last_name":"Scott","full_name":"Scott, Daryl A."},{"first_name":"Peter","last_name":"Scheiffele","full_name":"Scheiffele, Peter"},{"full_name":"Strømgaard, Kristian","first_name":"Kristian","last_name":"Strømgaard"},{"first_name":"Mehdi","last_name":"Tafti","full_name":"Tafti, Mehdi"},{"full_name":"Gassmann, Martin","last_name":"Gassmann","first_name":"Martin"},{"first_name":"Bernd","last_name":"Fakler","full_name":"Fakler, Bernd"},{"id":"499F3ABC-F248-11E8-B48F-1D18A9856A87","first_name":"Ryuichi","last_name":"Shigemoto","full_name":"Shigemoto, Ryuichi","orcid":"0000-0001-8761-9444"},{"last_name":"Bettler","first_name":"Bernhard","full_name":"Bettler, Bernhard"}],"intvolume":"        10","doi":"10.1126/sciadv.adk5462","file_date_updated":"2024-07-22T06:29:27Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_published":"2024-07-12T00:00:00Z","quality_controlled":"1","oa":1,"language":[{"iso":"eng"}],"publication_identifier":{"eissn":["2375-2548"]},"file":[{"access_level":"open_access","relation":"main_file","file_size":7241489,"creator":"dernst","file_id":"17287","file_name":"2024_ScienceAdv_Früh.pdf","success":1,"date_updated":"2024-07-22T06:29:27Z","checksum":"9cbc4501fcd4ba1c0811fd244031422b","date_created":"2024-07-22T06:29:27Z","content_type":"application/pdf"}],"abstract":[{"lang":"eng","text":"Adherens junction–associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed significantly decreased presynaptic GBR levels in Ajap1−/− and Ajap1W183C/+ mice. Consequently, these mice exhibited reduced GBR-mediated presynaptic inhibition at excitatory and inhibitory synapses, along with impaired synaptic plasticity. Our study reveals that AJAP1 enables the postsynaptic neuron to regulate the level of presynaptic GBR-mediated inhibition, supporting the clinical relevance of loss-of-function AJAP1 variants."}],"external_id":{"pmid":["38985877"]},"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"citation":{"mla":"Früh, Simon, et al. “Monoallelic de Novo AJAP1 Loss-of- Function Variants Disrupt Trans-Synaptic Control of Neurotransmitter Release.” <i>Science Advances</i>, vol. 10, no. 28, adk5462, American Association for the Advancement of Science, 2024, doi:<a href=\"https://doi.org/10.1126/sciadv.adk5462\">10.1126/sciadv.adk5462</a>.","ama":"Früh S, Boudkkazi S, Koppensteiner P, et al. Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release. <i>Science Advances</i>. 2024;10(28). doi:<a href=\"https://doi.org/10.1126/sciadv.adk5462\">10.1126/sciadv.adk5462</a>","ieee":"S. Früh <i>et al.</i>, “Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release,” <i>Science Advances</i>, vol. 10, no. 28. American Association for the Advancement of Science, 2024.","short":"S. Früh, S. Boudkkazi, P. Koppensteiner, V. Sereikaite, L.Y. Chen, D. Fernandez-Fernandez, P.D. Rem, D. Ulrich, J. Schwenk, Z. Chen, E.L. Monnier, T. Fritzius, S.M. Innocenti, V. Besseyrias, L. Trovò, M. Stawarski, E. Argilli, E.H. Sherr, B. Van Bon, E.J. Kamsteeg, M. Iascone, A. Pilotta, M.R. Cutrì, M.S. Azamian, A. Hernández-García, S.R. Lalani, J.A. Rosenfeld, X. Zhao, T.P. Vogel, H. Ona, D.A. Scott, P. Scheiffele, K. Strømgaard, M. Tafti, M. Gassmann, B. Fakler, R. Shigemoto, B. Bettler, Science Advances 10 (2024).","ista":"Früh S, Boudkkazi S, Koppensteiner P, Sereikaite V, Chen LY, Fernandez-Fernandez D, Rem PD, Ulrich D, Schwenk J, Chen Z, Monnier EL, Fritzius T, Innocenti SM, Besseyrias V, Trovò L, Stawarski M, Argilli E, Sherr EH, Van Bon B, Kamsteeg EJ, Iascone M, Pilotta A, Cutrì MR, Azamian MS, Hernández-García A, Lalani SR, Rosenfeld JA, Zhao X, Vogel TP, Ona H, Scott DA, Scheiffele P, Strømgaard K, Tafti M, Gassmann M, Fakler B, Shigemoto R, Bettler B. 2024. Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release. Science Advances. 10(28), adk5462.","chicago":"Früh, Simon, Sami Boudkkazi, Peter Koppensteiner, Vita Sereikaite, Li Yuan Chen, Diego Fernandez-Fernandez, Pascal D. Rem, et al. “Monoallelic de Novo AJAP1 Loss-of- Function Variants Disrupt Trans-Synaptic Control of Neurotransmitter Release.” <i>Science Advances</i>. American Association for the Advancement of Science, 2024. <a href=\"https://doi.org/10.1126/sciadv.adk5462\">https://doi.org/10.1126/sciadv.adk5462</a>.","apa":"Früh, S., Boudkkazi, S., Koppensteiner, P., Sereikaite, V., Chen, L. Y., Fernandez-Fernandez, D., … Bettler, B. (2024). Monoallelic de novo AJAP1 loss-of- function variants disrupt trans-synaptic control of neurotransmitter release. <i>Science Advances</i>. American Association for the Advancement of Science. <a href=\"https://doi.org/10.1126/sciadv.adk5462\">https://doi.org/10.1126/sciadv.adk5462</a>"},"publication_status":"published","year":"2024","article_number":"adk5462","date_created":"2024-07-21T22:01:01Z","ddc":["570"],"article_processing_charge":"Yes","department":[{"_id":"RySh"},{"_id":"PreCl"}],"publisher":"American Association for the Advancement of Science"}