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mGluR5 hypofunction is integral to glutamatergic dysregulation in schizophrenia

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Abstract

Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein–protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 phosphorylation) and here we show those of reduced mGluR5 signaling in schizophrenia. We find that reduced GluN2 phosphorylation can be precipitated by attenuated mGluR5 activity and that increased mGluR5 phosphorylation can result from decreased GluN function, suggesting a reciprocal interplay between the two pathways in schizophrenia. Interestingly, the patient group showed decreased mGluR5–GluN association (p < 0.01), a mechanistic basis for the reciprocal facilitation. In sum, we present the first direct evidence for mGluR5 hypoactivity, propose a reciprocal interplay between GluN and mGluR5 pathways as integral to glutamatergic dysregulation and suggest protein–protein interactions in mGluR5–GluN complexes as potential targets for intervention in schizophrenia.

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Acknowledgements

We express most heartfelt gratitude to the donors of postmortem brain tissues and their family members. This project was supported by RO1-MH075916 and P50-MH096891 (CH).

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Authors and Affiliations

  1. Department of Physiology, Pharmacology and Neuroscience, City University of New York School of Medicine, New York, NY, 10031, USA

    Hoau-Yan Wang, Andrew Tom, Amber Khan & Kuo-Chieh Lee

  2. Department of Biology and Neuroscience, Graduate School of the City University of New York, New York, NY, 10016, USA

    Hoau-Yan Wang & Amber Khan

  3. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, 19104-3403, USA

    Mathew L. MacDonald, Karin E. Borgmann-Winter, Anamika Banerjee, Raquel E. Gur & Chang-Gyu Hahn

  4. Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Karin E. Borgmann-Winter

  5. The Center for Applied Genomics, The Children’s Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Patrick Sleiman

  6. Department of Psychiatry, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Panos Roussos

  7. Department of Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, CA, 90007, USA

    Steven J. Siegel

  8. Department of Basic Pharmaceutical Sciences, High Point University, High Point, NC, 27106, USA

    Scott E. Hemby

  9. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Warren B. Bilker

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  1. Hoau-Yan Wang
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Wang, HY., MacDonald, M.L., Borgmann-Winter, K.E. et al. mGluR5 hypofunction is integral to glutamatergic dysregulation in schizophrenia. Mol Psychiatry 25, 750–760 (2020). https://doi.org/10.1038/s41380-018-0234-y

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