Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Institute of Physiology II, University of Freiburg, Hermann-Herderstrasse 7, 79104 Freiburg, Germany.
Sci Adv. 2024 Jul 12;10(28):eadk5462. doi: 10.1126/sciadv.adk5462. Epub 2024 Jul 10.
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 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 and 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 variants.
黏着斑连接相关蛋白 1（AJAP1）与脑部疾病有关；然而，其致病机制尚未确定。AJAP1 在神经元中广泛表达，并与γ-氨基丁酸 B 型受体（GBRs）结合，GBRs 在大脑中的大多数突触处抑制神经递质的释放。在这里，我们表明 AJAP1 选择性地在树突中表达，并通过跨突触将 GBR 募集到表达 AJAP1 的神经元的突触前部位。我们已经在癫痫和/或神经发育障碍患者中鉴定出几种单等位基因变体。具体来说，我们表明变体 p.(W183C) 缺乏与 GBR 的结合能力，从而无法募集它们。超微结构分析显示 和 小鼠中的突触前 GBR 水平显著降低。因此，这些小鼠在兴奋性和抑制性突触中表现出 GBR 介导的抑制作用减弱，以及突触可塑性受损。我们的研究表明，AJAP1 使突触后神经元能够调节突触前 GBR 介导的抑制水平，支持功能丧失 变体的临床相关性。
