Monoallelic de novo <i>AJAP1</i> loss-of-function variants disrupt trans-synaptic control of neurotransmitter release-Reference-Cited by-同舟云学术

Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release

Published:2024-07-12 Issue:28 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Früh Simon¹^ORCID,Boudkkazi Sami²,Koppensteiner Peter³^ORCID,Sereikaite Vita⁴,Chen Li-Yuan⁵^ORCID,Fernandez-Fernandez Diego¹^ORCID,Rem Pascal D.¹^ORCID,Ulrich Daniel¹,Schwenk Jochen²^ORCID,Chen Ziyang⁴,Le Monnier Elodie³^ORCID,Fritzius Thorsten¹^ORCID,Innocenti Sabrina M.⁶,Besseyrias Valérie¹,Trovò Luca¹^ORCID,Stawarski Michal¹^ORCID,Argilli Emanuela⁷⁸^ORCID,Sherr Elliott H.⁷⁸^ORCID,van Bon Bregje⁹,Kamsteeg Erik-Jan⁹^ORCID,Iascone Maria¹⁰^ORCID,Pilotta Alba¹¹^ORCID,Cutrì Maria R.¹¹^ORCID,Azamian Mahshid S.¹²^ORCID,Hernández-García Andrés¹²,Lalani Seema R.¹²,Rosenfeld Jill A.¹²^ORCID,Zhao Xiaonan¹²¹³^ORCID,Vogel Tiphanie P.¹⁴¹⁵^ORCID,Ona Herda¹⁴¹⁵,Scott Daryl A.¹²¹⁶^ORCID,Scheiffele Peter⁶^ORCID,Strømgaard Kristian⁴^ORCID,Tafti Mehdi⁵^ORCID,Gassmann Martin¹^ORCID,Fakler Bernd²^ORCID,Shigemoto Ryuichi³^ORCID,Bettler Bernhard¹^ORCID

Affiliation:

1. Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.

2. Institute of Physiology II, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany.

3. Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria.

4. Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.

5. Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 7, 1005 Lausanne, Switzerland.

6. Biocenter, University of Basel, Spitalstrasse 41, 4056 Basel, Switzerland.

7. Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.

8. Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

9. Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525, Netherlands.

10. Laboratorio Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.

11. UO Pediatria, Spedali Civili, Brescia, Italy.

12. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

13. Baylor Genetics, Houston, TX 77021, USA.

14. Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.

15. Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.

16. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

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 Ajap1 W183C/+ 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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adk5462

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