Journal
SCIENCE
Volume 338, Issue 6103, Pages 128-132Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1224159
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Funding
- Dutch Organization for Medical Sciences (ZonMw)
- Life Sciences (ALW)
- Senter (NeuroBasic)
- Prinses Beatrix Fonds
- European Research Council (European Community)
- SystemsX grant
- EU-AIMS (European Autism Interventions)
- Innovative Medicines Initiative [115300]
- European Union
- European Federation of Pharmaceutical Industries and Associations companies'
- NCCR Synapsy
- Swiss National Science Foundation
- Kanton Basel-Stadt
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The genetic heterogeneity of autism poses a major challenge for identifying mechanism-based treatments. A number of rare mutations are associated with autism, and it is unclear whether these result in common neuronal alterations. Monogenic syndromes, such as fragile X, include autism as one of their multifaceted symptoms and have revealed specific defects in synaptic plasticity. We discovered an unexpected convergence of synaptic pathophysiology in a nonsyndromic form of autism with those in fragile X syndrome. Neuroligin-3 knockout mice (a model for nonsyndromic autism) exhibited disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor-dependent synaptic plasticity, a hallmark of fragile X. These phenotypes could be rescued by reexpression of neuroligin-3 in juvenile mice, highlighting the possibility of reverting neuronal circuit alterations in autism after the completion of development.
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