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Altered Expression of CDC42 Signaling Pathway Components in Cortical Layer 3 Pyramidal Cells in Schizophrenia
Datta D, Arion D, Corradi JP and Lewis DA
Biological Psychiatry, 2015, Published Online


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 CDC42 (cell division cycle 42)-CDC42 effector protein signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects with schizophrenia.  Investigators in the Translational Neuroscience Program examined the integrity in schizophrenia of the CDC42-PAK-LIMK signaling pathway in a layer- and cell type-specific fashion in DLPFC deep layer 3.

Using laser microdissection, Dibyadeep Datta and his collaborators collected samples of DLPFC deep layer 3 from 56 matched pairs of schizophrenia and comparison subjects and measured levels of CDC42-PAK-LIMK pathway mRNAs by qPCR. These same transcripts were also quantified by microarray in samples of individually microdissected deep layer 3 pyramidal cells from a subset of the same subjects and from antipsychotic exposed monkeys.  

The results of this study showed that relative to comparison subjects, CDC42EP4, LIMK1, LIMK2, ARHGDIA and PAK3 mRNA levels were significantly up-regulated in schizophrenia subjects in both laminar and cellular samples. In contrast, CDC42 and PAK1 mRNA levels were significantly down-regulated specifically in deep layer 3 pyramidal cells. These differences were not attributable to psychotropic medications or other comorbid factors.

Findings from this project and prior studies converge on synergistic alterations in the CDC42 signaling pathway that could destabilize actin dynamics and produce spine deficits preferentially in deep layer 3 pyramidal cells in schizophrenia.  

Contributors:
Dibyadeep Datta, BA, Dominique Arion, PhD and David A. Lewis, MD (Department of Psychiatry, University of Pittsburgh School of Medicine)

John P Corradi, PhD (Bristol-Myers Squibb, USA)

This article appeared online in the journal Biological Psychiatry.  Click here for the abstract.