%0 Journal Article
%T Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.
%A Früh S
%A Boudkkazi S
%A Koppensteiner P
%A Sereikaite V
%A Chen LY
%A Fernandez-Fernandez D
%A Rem PD
%A Ulrich D
%A Schwenk J
%A Chen Z
%A Le Monnier E
%A Fritzius T
%A Innocenti SM
%A Besseyrias V
%A Trovò L
%A Stawarski M
%A Argilli E
%A Sherr EH
%A van Bon B
%A Kamsteeg EJ
%A Iascone M
%A Pilotta A
%A Cutrì MR
%A Azamian MS
%A Hernández-García A
%A Lalani SR
%A Rosenfeld JA
%A Zhao X
%A Vogel TP
%A Ona H
%A Scott DA
%A Scheiffele P
%A Strømgaard K
%A Tafti M
%A Gassmann M
%A Fakler B
%A Shigemoto R
%A Bettler B
%J Sci Adv
%V 10
%N 28
%D 2024 Jul 12
%M 38985877
%F 14.957
%R 10.1126/sciadv.adk5462
%X 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.