title: Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia.
abstract: BACKGROUND
  Impaired glutamatergic signaling is believed to underlie auditory cortex pyramidal neuron dendritic spine loss and auditory symptoms in schizophrenia. Many schizophrenia risk loci converge on the synaptic glutamate signaling network. We therefore hypothesized that alterations in glutamate signaling protein expression and co-expression network features are present in schizophrenia.
  
  
  METHODS
  Gray matter homogenates were prepared from auditory cortex gray matter of 22 schizophrenia and 23 matched control subjects, a subset of whom had been previously assessed for dendritic spine density. One hundred fifty-five selected synaptic proteins were quantified by targeted mass spectrometry. Protein co-expression networks were constructed using weighted gene co-expression network analysis.
  
  
  RESULTS
  Proteins with evidence for altered expression in schizophrenia were significantly enriched for glutamate signaling pathway proteins (GRIA4, GRIA3, ATP1A3, and GNAQ). Synaptic protein co-expression was significantly decreased in schizophrenia with the exception of a small group of postsynaptic density proteins, whose co-expression increased and inversely correlated with spine density in schizophrenia subjects.
  
  
  CONCLUSIONS
  We observed alterations in the expression of glutamate signaling pathway proteins. Among these, the novel observation of reduced ATP1A3 expression is supported by strong genetic evidence indicating it may contribute to psychosis and cognitive impairment phenotypes. The observations of altered protein network topology further highlight the complexity of glutamate signaling network pathology in schizophrenia and provide a framework for evaluating future experiments to model the contribution of genetic risk to disease pathology.
authors.affiliation: Departments of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: MacDonald
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Departments of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jason
authors.initials: J
authors.lastname: Newman
authors.affiliation: Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: Scott
authors.initials: S
authors.lastname: Hemby
authors.affiliation: Departments of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Peter
authors.initials: P
authors.lastname: Penzes
authors.affiliation: Departments of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Biomedical Mass Spectrometry Center, University of Pittsburgh, Pittsburgh, Pennsylvania; Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Yates
authors.affiliation: Departments of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania; Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.. Electronic address: sweetra@upmc.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sweet
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001303:Auditory Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D016022:Case-Control Studies; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D011180:Postmortem Changes; D060066:Protein Interaction Maps / Q000187:drug effects; D012559:Schizophrenia / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D055815:Young Adult
chemical_list: C488756:ATP1A3 protein, human; D014150:Antipsychotic Agents; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D018698:Glutamic Acid; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Auditory cortex; Glutamate; Postmortem; Proteomics; Schizophrenia; Spine