title: Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia.
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.
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Physiology, Pharmacology and Neuroscience, City University of New York Medical School, New York, NY, USA.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Borgmann-Winter
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: MacDonald
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kaprielian
authors.affiliation: Department of Physiology, Pharmacology and Neuroscience, City University of New York Medical School, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Stucky
authors.affiliation: Department of Physiology, Pharmacology and Neuroscience, City University of New York Medical School, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kvasic
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Egbujo
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ray
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Hemby
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Siegel
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Arnold
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sleiman
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chang
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: C-G
authors.initials: CG
authors.lastname: Hahn
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D010766:Phosphorylation; D057907:Post-Synaptic Density / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D060066:Protein Interaction Maps; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases