Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
    • Subject Terms:
      Neurotransmitter Agents*/metabolism ; Synapses*/metabolism ; Synaptic Transmission*; Animals ; Female ; Humans ; Male ; Mice ; Alleles ; Epilepsy/metabolism ; Epilepsy/genetics ; Epilepsy/pathology ; Loss of Function Mutation ; Mice, Knockout ; Neurodevelopmental Disorders/metabolism ; Neurodevelopmental Disorders/genetics ; Neurodevelopmental Disorders/pathology ; Neuronal Plasticity ; Neurons/metabolism ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism
    • 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 Ajap1 W183C/+ 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.
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    • Accession Number:
      0 (Neurotransmitter Agents)
      0 (AJAP1 protein, human)
      0 (Cell Adhesion Molecules)
    • Publication Date:
      Date Created: 20240710 Date Completed: 20240710 Latest Revision: 20240806
    • Publication Date:
      20240806
    • Accession Number:
      PMC11235169
    • Accession Number:
      10.1126/sciadv.adk5462
    • Accession Number:
      38985877