1. Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.
- Author
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Früh, Simon, Boudkkazi, Sami, Koppensteiner, Peter, Sereikaite, Vita, Chen, Li-Yuan, Fernandez-Fernandez, Diego, Rem, Pascal, Ulrich, Daniel, Schwenk, Jochen, Chen, Ziyang, Le Monnier, Elodie, Fritzius, Thorsten, Innocenti, Sabrina, Besseyrias, Valérie, Trovò, Luca, Stawarski, Michal, Argilli, Emanuela, Sherr, Elliott, van Bon, Bregje, Kamsteeg, Erik-Jan, Iascone, Maria, Pilotta, Alba, Cutrì, Maria, Azamian, Mahshid, Hernández-García, Andrés, Lalani, Seema, Rosenfeld, Jill, Zhao, Xiaonan, Vogel, Tiphanie, Ona, Herda, Scott, Daryl, Scheiffele, Peter, Strømgaard, Kristian, Tafti, Mehdi, Gassmann, Martin, Fakler, Bernd, Shigemoto, Ryuichi, and Bettler, Bernhard
- Subjects
Animals ,Female ,Humans ,Male ,Mice ,Alleles ,Epilepsy ,Loss of Function Mutation ,Mice ,Knockout ,Neurodevelopmental Disorders ,Neuronal Plasticity ,Neurons ,Neurotransmitter Agents ,Synapses ,Synaptic Transmission ,Cell Adhesion Molecules - 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.
- Published
- 2024