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ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior

Molecular Psychiatry volume 24, pages 1902–1919 (2019)Cite this article

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Abstract

The functional characterization of the GPCR interactome has predominantly focused on intracellular binding partners; however, the recent emergence of transsynaptic GPCR complexes represents an additional dimension to GPCR function that has previously been unaccounted for in drug discovery. Here, we characterize ELFN2 as a novel postsynaptic adhesion molecule with a distinct expression pattern throughout the brain and a selective binding with group III metabotropic glutamate receptors (mGluRs) in trans. Using a transcellular GPCR signaling platform, we report that ELFN2 critically alters group III mGluR secondary messenger signaling by directly altering G protein coupling kinetics and efficacy. Loss of ELFN2 in mice results in the selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission. Elfn2 knockout (Elfn2 KO) mice also feature a range of neuropsychiatric manifestations including seizure susceptibility, hyperactivity, and anxiety/compulsivity, which can be rescued by pharmacological augmentation of group III mGluRs. Thus, we conclude that extracellular transsynaptic scaffolding by ELFN2 in the brain is a cardinal organizational feature of group III mGluRs essential for their signaling properties and brain function.

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Acknowledgements

This work was supported by NIH Grants EY028033 and MH105482 (to KAM). HAD is the recipient of a Canadian Institutes of Health Research Postdoctoral Fellowship award. SZ is the recipient of National Institute of Health F32 Award DA048579.

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  1. Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, 33458, USA

    Henry A. Dunn, Stefano Zucca, Maria Dao, Cesare Orlandi & Kirill A. Martemyanov

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All authors designed research; HAD, SZ, MD, and CO performed research; all authors analyzed data; and HAD and KAM wrote the paper with the input from all authors.

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Correspondence to Kirill A. Martemyanov.

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Dunn, H.A., Zucca, S., Dao, M. et al. ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior. Mol Psychiatry 24, 1902–1919 (2019). https://doi.org/10.1038/s41380-019-0512-3

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