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Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia

Molecular Psychiatry volume 20, pages 1091–1100 (2015)Cite this article

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Abstract

Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity that in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor-type tyrosine-protein phosphatase-α (RPTPα) and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome-wide association study results, incorporating 13 394 cases and 34 676 controls. We found no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a protein–protein interaction-based network centered on Src showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose Src as a nodal point of convergent dysregulations affecting NMDA receptor pathway via protein–protein associations.

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Acknowledgements

We express most heartfelt gratitude to the donors of post-mortem brain tissues and their family members. We also thank Dr Wade Berrettini for reading this manuscript and making valuable suggestions. This project was supported by the RO1-MH075916 and R01MH059852 (C-GH), grants from NARSAD and Stanley Medical Research Institute (to C-GH), RO1MH07462 (to SJS), RO1MH074313 and a grant from the Stanley Medical Research Institute (to SEH).

Author Contributions

AB performed biochemical fractionations. AB and H-YW performed all other experiments including immunoprecipitation, receptor and kinase activation assays with help from KEB-W, MLM, AS, HK, JK CE, RR and KT. PS, XC and HH conducted network analysis of GWAS data; SEH and SJS conducted antipsychotic treatment of rhesus monkeys and mice. The post-mortem tissue and brains were collected by SEA, KT and REG, who also ensured the integrity of post-mortem brain tissues. PS, XC and HH conducted analyses of genetic data. AB and C-GH performed all other data analyses. C-GH conceived of and directed this study. The manuscript was written by AB, KBW, KT and C-GH and edited by all authors.

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  1. A Banerjee and H-Y Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    A Banerjee, K E Borgmann-Winter, M L MacDonald, H Kaprielian, C Egbujo, R Ray, K Talbot, S J Siegel, S E Arnold, R E Gur & C-G Hahn

  2. Department of Physiology, Pharmacology and Neuroscience, City University of New York Medical School, New York, NY, USA

    H-Y Wang, A Stucky & J Kvasic

  3. Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    S E Hemby

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

    P Sleiman, X Chang & H Hakonarson

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  1. A Banerjee
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Correspondence to C-G Hahn.

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Banerjee, A., Wang, HY., Borgmann-Winter, K. et al. Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia. Mol Psychiatry 20, 1091–1100 (2015). https://doi.org/10.1038/mp.2014.115

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