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Autism-Associated Neuroligin-3 Mutations Commonly Disrupt Tonic Endocannabinoid Signaling

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Földy, Csaba, Malenka, Robert C., Südhof, Thomas C.·2013·Neuron

Abstract

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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Crossref · 10.1016/j.neuron.2013.02.036

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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)
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
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 › 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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