Article, 2024
Monoallelic de novo AJAP1 loss-of-function variants disrupt trans-synaptic control of neurotransmitter release
Science Advances,
ISSN
2375-2548,
Volume 10,
28,
Page eadk5462,
10.1126/sciadv.adk5462
Contributors
Früh, Simon
0000-0001-6804-5385
[1]
Boudkkazi, Sami
[2]
Koppensteiner, Peter
0000-0002-3509-1948
[3]
Sereikaite, Vita
0000-0001-7497-4965
[4]
Chen, Li-Yuan
[5]
Fernandez-Fernandez, Diego
[1]
Rem, Pascal Dominic
[1]
Ulrich, Daniel
[1]
Schwenk, Jochen
[2]
Chen, Ziyang
[4]
Le Monnier, Elodie
[3]
Fritzius, Thorsten
0000-0002-3597-6623
[1]
Innocenti, Sabrina Milena
[1]
Besseyrias, Valerie
[1]
Trovò, Luca
0000-0002-5864-3776
[1]
Stawarski, Michal
0000-0002-9889-0085
[1]
Argilli, Emanuela
0000-0002-6575-7501
[6]
Sherr, Elliott H
0000-0002-4118-5385
[6]
Van Bon, Bregje W M
0000-0003-2234-0105
[7]
Kamsteeg, Erik-Jan
[7]
Iascone, Maria Rosaria
0000-0002-4707-212X
[8]
Pilotta, Alba
[9]
Cutrì, Maria R.
[9]
Azamian, Mahshid Sababi
0000-0002-8543-8284
[10]
Hernández-García, Andrés
[10]
Lalani, Seema R
0000-0003-0707-657X
[10]
Rosenfeld, Jill A.
[10]
Zhao, Xiaonan
[10]
[11]
Vogel, Tiphanie Phillips
[10]
[12]
Ona, Herda
[10]
[12]
Scott, Daryl Armstrong
[10]
Scheiffele, Peter
0000-0002-9516-9399
[1]
Strømgaard, Kristian
0000-0003-2206-4737
[4]
Tafti, Mehdi
[5]
Gassmann, Martin
[1]
Fakler, Bernd
0000-0001-7264-6423
[2]
Shigemoto, Ryuichi
0000-0001-8761-9444
[3]
Bettler, Bernhard
0000-0003-0842-8207
(Corresponding author)
[1]
Affiliations
- [1]
University of Basel
[NORA names:
Switzerland; Europe, Non-EU; OECD];
- [2]
University of Freiburg
[NORA names:
Germany; Europe, EU; OECD];
- [3]
Institute of Science and Technology Austria
[NORA names:
Austria; Europe, EU; OECD];
- [4]
University of Copenhagen
[NORA names:
KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
- [5]
University of Lausanne
[NORA names:
Switzerland; Europe, Non-EU; OECD];
(... more)
- [6]
University of California, San Francisco
[NORA names:
United States; America, North; OECD];
- [7]
Radboud University Nijmegen Medical Centre
[NORA names:
Netherlands; Europe, EU; OECD];
- [8]
Ospedale Papa Giovanni XXIII
[NORA names:
Italy; Europe, EU; OECD];
- [9]
Spedali Civili di Brescia
[NORA names:
Italy; Europe, EU; OECD];
- [10]
Baylor College of Medicine
[NORA names:
United States; America, North; OECD];
- [11]
Baylor Genetics
[NORA names:
United States; America, North; OECD];
- [12]
Texas Children's Hospital
[NORA names:
United States; America, North; OECD]
(less)
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.
Keywords
B receptor,
GBR,
Monoallelic,
adherens,
adherens junction-associated protein 1,
analysis,
binding,
brain,
brain diseases,
clinical relevance,
control of neurotransmitter release,
dendrites,
disease,
disorders,
epilepsy,
impaired synaptic plasticity,
inability,
individuals,
inhibit neurotransmitter release,
inhibition,
inhibitory synapses,
levels,
loss-of-function variants,
mechanism,
mice,
neurodevelopmental disorders,
neurons,
neurotransmitter release,
pathogenic mechanisms,
plasticity,
postsynaptic neurons,
presynaptic inhibition,
presynaptic sites,
protein 1,
release,
sites,
study,
synapses,
synaptic plasticity,
trans-synaptically,
type B receptor,
ultrastructural analysis,
variant p.,
variants
Funders
Data Provider: Digital Science