Altered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia

Biol Psychiatry. 2015 Dec 1;78(11):775-85. doi: 10.1016/j.biopsych.2015.03.030. Epub 2015 Apr 11.


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.

Keywords: Actin cytoskeleton; CDC42; Dendritic spine; Prefrontal cortex; Schizophrenia; mRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antipsychotic Agents / pharmacology
  • Benzodiazepines / pharmacology
  • Cytoskeletal Proteins
  • Female
  • GTP-Binding Protein Regulators / genetics
  • GTP-Binding Protein Regulators / metabolism
  • Gene Expression Regulation / drug effects
  • Haloperidol / pharmacology
  • Humans
  • Laser Capture Microdissection
  • Lim Kinases / genetics
  • Lim Kinases / metabolism
  • Macaca fascicularis
  • Male
  • Middle Aged
  • Olanzapine
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Prefrontal Cortex / pathology
  • RNA-Binding Proteins
  • Schizophrenia / pathology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism*
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism
  • rho GTP-Binding Proteins
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / genetics
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / metabolism


  • ARHGDIA protein, human
  • Antipsychotic Agents
  • CDC42EP4 protein, human
  • Cytoskeletal Proteins
  • GTP-Binding Protein Regulators
  • RNA-Binding Proteins
  • rho Guanine Nucleotide Dissociation Inhibitor alpha
  • Benzodiazepines
  • LIMK1 protein, human
  • LIMK2 protein, human
  • Lim Kinases
  • PAK3 protein, human
  • p21-Activated Kinases
  • cdc42 GTP-Binding Protein
  • rho GTP-Binding Proteins
  • Haloperidol
  • Olanzapine