Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-02

AUTHORS

Soham Chanda, Jason Aoto, Sung-Jin Lee, Marius Wernig, Thomas C. Südhof

ABSTRACT

Neuroligins are postsynaptic cell-adhesion molecules that bind to presynaptic neurexins. Although the general synaptic role of neuroligins is undisputed, their specific functions at a synapse remain unclear, even controversial. Moreover, many neuroligin gene mutations were associated with autism, but the pathophysiological relevance of these mutations is often unknown, and their mechanisms of action uninvestigated. Here, we examine the synaptic effects of an autism-associated neuroligin-4 substitution (called R704C), which mutates a cytoplasmic arginine residue that is conserved in all neuroligins. We show that the R704C mutation, when introduced into neuroligin-3, enhances the interaction between neuroligin-3 and AMPA receptors, increases AMPA-receptor internalization and decreases postsynaptic AMPA-receptor levels. When introduced into neuroligin-4, conversely, the R704C mutation unexpectedly elevated AMPA-receptor-mediated synaptic responses. These results suggest a general functional link between neuroligins and AMPA receptors, indicate that both neuroligin-3 and -4 act at excitatory synapses but perform surprisingly distinct functions, and demonstrate that the R704C mutation significantly impairs the normal function of neuroligin-4, thereby validating its pathogenicity. More... »

PAGES

169-177

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/mp.2015.20

DOI

http://dx.doi.org/10.1038/mp.2015.20

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https://app.dimensions.ai/details/publication/pub.1021738318

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25778475


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