title: Altered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia.
abstract: BACKGROUND
  Cognitive dysfunction in schizophrenia is associated with a lower density of dendritic spines on deep layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC). These alterations appear to reflect dysregulation of the actin cytoskeleton required for spine formation and maintenance. Consistent with this idea, altered expression of genes in the cell division cycle 42 (CDC42)-CDC42 effector protein (CDC42EP) signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects with schizophrenia. We examined the integrity of the CDC42-p21-activated serine/threonine protein kinases (PAK)-LIM domain-containing serine/threonine protein kinases (LIMK) signaling pathway in schizophrenia in a layer-specific and cell type-specific fashion in DLPFC deep layer 3.
  
  
  METHODS
  Using laser microdissection, samples of DLPFC deep layer 3 were collected from 56 matched pairs of subjects with schizophrenia and comparison subjects, and levels of CDC42-PAK-LIMK pathway messenger RNAs were measured by quantitative polymerase chain reaction. These same transcripts also were quantified by microarray in samples of individually microdissected deep layer 3 pyramidal cells from a subset of the same subjects and from monkeys exposed to antipsychotics.
  
  
  RESULTS
  Relative to comparison subjects, CDC42EP4, LIMK1, LIMK2, ARHGDIA, and PAK3 messenger RNA levels were significantly upregulated in subjects with schizophrenia in laminar and cellular samples. In contrast, CDC42 and PAK1 messenger RNA levels were significantly downregulated specifically in deep layer 3 pyramidal cells. These differences were not attributable to psychotropic medications or other comorbid factors.
  
  
  CONCLUSIONS
  Findings from the present and prior studies converge on synergistic alterations in CDC42 signaling pathway that could destabilize actin dynamics and produce spine deficits preferentially in deep layer 3 pyramidal cells in schizophrenia.
authors.affiliation: Departments of Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Dibyadeep
authors.initials: D
authors.lastname: Datta
authors.affiliation: Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Dominique
authors.initials: D
authors.lastname: Arion
authors.affiliation: Department of Applied Genomics (JPC), Bristol-Myers Squibb, New York, New York.
authors.forename: John P
authors.initials: JP
authors.lastname: Corradi
authors.affiliation: Departments of Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: lewisda@upmc.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D003598:Cytoskeletal Proteins; D005260:Female; D020555:GTP-Binding Protein Regulators / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D061346:Laser Capture Microdissection; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016601:RNA-Binding Proteins; D012559:Schizophrenia / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C569638:ARHGDIA protein, human; D014150:Antipsychotic Agents; C422985:CDC42EP4 protein, human; D003598:Cytoskeletal Proteins; D020555:GTP-Binding Protein Regulators; D016601:RNA-Binding Proteins; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D001569:Benzodiazepines; C515892:LIMK1 protein, human; C102895:LIMK2 protein, human; D054461:Lim Kinases; C515911:PAK3 protein, human; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D006220:Haloperidol; D000077152:Olanzapine
keywords: Actin cytoskeleton; CDC42; Dendritic spine; Prefrontal cortex; Schizophrenia; mRNA