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.
摘要:
粘附蛋白连接相关蛋白1(AJAP1)与脑部疾病有关;然而,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(GBR)结合,抑制大脑中大部分突触的神经递质释放。这里,我们显示AJAP1在树突中选择性表达,并跨突触地将GBR募集到表达AJAP1的神经元的突触前位点。我们已经在患有癫痫和/或神经发育障碍的个体中鉴定了几种单等位基因AJAP1变体。具体来说,我们显示变体p。(W183C)缺乏与GBR的结合,导致无法招募他们。超微结构分析显示,Ajap1-/-和Ajap1W183C/小鼠的突触前GBR水平显着降低。因此,这些小鼠在兴奋性和抑制性突触表现出减少的GBR介导的突触前抑制,伴随着突触可塑性受损。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,支持功能丧失型AJAP1变异的临床相关性。