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Autism-Associated Neuroligin-3 Mutations Commonly Disrupt Tonic Endocannabinoid Signaling
Open accessAbstract
Neuroligins are postsynaptic cell-adhesion molecules that interact with presynaptic neurexins. Rare mutations in neuroligins and neurexins predispose to autism, including a neuroligin-3 amino acid substitution (R451C) and a neuroligin-3 deletion. Previous analyses showed that neuroligin-3 R451C-knockin mice exhibit robust synaptic phenotypes but failed to uncover major changes in neuroligin-3 knockout mice, questioning the notion that a common synaptic mechanism mediates autism pathogenesis in patients with these mutations. Here, we used paired recordings in mice carrying these mutations to measure synaptic transmission at GABAergic synapses formed by hippocampal parvalbumin- and cholecystokinin-expressing basket cells onto pyramidal neurons. We demonstrate that in addition to unique gain-of-function effects produced by the neuroligin-3 R451C-knockin but not the neuroligin-3 knockout mutation, both mutations dramatically impaired tonic but not phasic endocannabinoid signaling. Our data thus suggest that neuroligin-3 is specifically required for tonic endocannabinoid signaling, raising the possibility that alterations in endocannabinoid signaling may contribute to autism pathophysiology.
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“For example, mutations in neuroligins, a family of ASD-linked synaptic adhesion proteins, impair tonic endocannabinoid signaling.34”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [34]
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Metadata
- Authors
- Földy, C., Malenka, R. C., & Südhof, T. C.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Földy, Csaba
- Südhof, Thomas C.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 78
- Issue
- 3
- Pages
- 498-509
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3663050
- OpenAlex
- W2142679888
- Cited by
- 287
- References
- 55
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 12 · 2023: 21 · 2022: 25 · 2021: 23 · 2020: 30 · 2019: 19 · 2018: 20 · 2017: 27 · 2016: 24 · 2015: 32 · 2014: 23 · 2013: 8
- FWCI
- 14.07
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-07-10)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Simons Foundation
- National Institute of Mental Health (P50MH086403)
- National Institute on Drug Abuse (R01DA030379, K99DA034029)
- National Institute of Neurological Disorders and Stroke (NS069375, P30NS069375)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Keywords
- neuroligin-3, autism spectrum disorder, GABAergic synapses, basket cells, parvalbumin, cholecystokinin, synaptic transmission, gain-of-function, neurexin, autism pathogenesis
- MeSH terms
- Animals, Cells, Cultured, Cholecystokinin, Hippocampus, Membrane Proteins, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Synaptic Transmission, Neurons, Parvalbumins, Synapses, Signal Transduction, Cell Adhesion Molecules, Neuronal, Mice, Gene Knock-In Techniques, GABAergic Neurons, Endocannabinoids
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