{Reference Type}: Journal Article
{Title}: Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.
{Author}: Früh S;Boudkkazi S;Koppensteiner P;Sereikaite V;Chen LY;Fernandez-Fernandez D;Rem PD;Ulrich D;Schwenk J;Chen Z;Le Monnier E;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;
{Journal}: Sci Adv
{Volume}: 10
{Issue}: 28
{Year}: 2024 Jul 12
{Factor}: 14.957
{DOI}: 10.1126/sciadv.adk5462
{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.