Article, 2024

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

Science Advances, ISSN 2375-2548, Volume 10, 28, 10.1126/sciadv.adk5462

Contributors

Fruh S. [1] Boudkkazi S. [2] Koppensteiner P. [3] Sereikaite V. 0000-0001-7497-4965 [4] Chen L.-Y. [5] Fernandez-Fernandez D. [1] Rem P.D. [1] Ulrich D. [1] Schwenk J.M. 0000-0001-8141-8449 [2] Chen Z. [4] Monnier E.L. [3] Fritzius T. [1] Innocenti S.M. [6] Besseyrias V. [1] Trovo L. [1] Stawarski M. [1] Argilli E. [7] Sherr E.H. [7] Van Bon B.W.M. [8] Kamsteeg E.-J. [8] Iascone M. 0000-0002-4707-212X [9] Pilotta A. [10] Cutri M.R. [10] Azamian M.S. 0000-0002-8543-8284 [11] Hernandez-Garcia A. [11] Lalani S.R. [11] Rosenfeld J.A. 0000-0001-5664-7987 [11] Zhao X. [11] [12] Vogel T.P. [11] [13] Ona H. [11] [13] Scott D.A. 0000-0003-1460-5169 [11] Scheiffele P. [6] Stromgaard K. 0000-0003-2206-4737 [4] Tafti M. 0000-0002-6997-3914 [5] Gassmann M. [1] Fakler B. [2] Shigemoto R. [3] Bettler B. 0000-0003-0842-8207 (Corresponding author) [1]

Affiliations

  1. [1] University of Basel
    2. [NORA names: Switzerland; Europe, Non-EU; OECD];
  2. [2] Albert-Ludwigs-Universität
    3. [NORA names: Germany; Europe, EU; OECD];
  3. [3] Institute of Science and Technology Austria
    4. [NORA names: Austria; Europe, EU; OECD];
  4. [4] University of Copenhagen
    5. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  5. [5] University of Lausanne
    6. [NORA names: Switzerland; Europe, Non-EU; OECD];

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 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.

Data Provider: Elsevier

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