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

Molecular Psychiatry volume 21, pages 169–177 (2016)Cite this article

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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.

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Acknowledgements

We thank Jeesun Kim, Bing Wu and Yoon Seok Kim for their help during the project. This paper was supported by grants from the NIH (R37-MH052804 to TCS; MH092931 to MW), an NIH K99 award (MH103531-01 to JA) and a postdoctoral grant award (Stanford, ChEM-H112878 to SC). MW is a New York Stem Cell Foundation-Robertson Investigator and a Tashia and John Morgridge Faculty Scholar.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA

    S Chanda, J Aoto, S-J Lee & T C Südhof

  2. Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    S Chanda & M Wernig

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  1. S Chanda
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  2. J Aoto
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Correspondence to T C Südhof.

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Chanda, S., Aoto, J., Lee, SJ. et al. Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking. Mol Psychiatry 21, 169–177 (2016). https://doi.org/10.1038/mp.2015.20

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