title: Altered Expression of ARP2/3 Complex Signaling Pathway Genes in Prefrontal Layer 3 Pyramidal Cells in Schizophrenia.
abstract: OBJECTIVE
  Lower dendritic spine density on layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) appears to contribute to cognitive dysfunction in schizophrenia, whereas psychosis is associated with excessive dopamine release in the striatum. These findings may be related via excitatory projections from the DLPFC to the ventral mesencephalon, the location of dopamine cells projecting to the striatum. Consistent with this hypothesis, deletion of the actin-related protein-2/3 (ARP2/3) complex, which regulates the actin cytoskeleton supporting dendritic spines, produced spine loss in cortical pyramidal cells and striatal hyperdopaminergia in mice. The authors sought to determine whether the ARP2/3 complex is altered in schizophrenia.
  
  
  METHODS
  In matched pairs of schizophrenia and comparison subjects, transcript levels of ARP2/3 complex signaling pathway were assessed in laser-microdissected DLPFC layer 3 and 5 pyramidal cells and layer 3 parvalbumin interneurons, and in total DLPFC gray matter.
  
  
  RESULTS
  Transcript levels of ARP2/3 complex subunits and of nucleation promotion factors that regulate the ARP2/3 complex were significantly lower in DLPFC layer 3 and 5 pyramidal cells in schizophrenia. In contrast, these transcripts were unaltered, or only modestly changed, in parvalbumin interneurons and DLPFC gray matter.
  
  
  CONCLUSIONS
  Down-regulation of the ARP2/3 complex signaling pathway, a common final pathway for multiple signaling cascades that regulate the actin cytoskeleton, would compromise the structural stability of spines, leading to their loss. In concert with findings from deletion of the ARP2/3 complex in mice, these findings support the idea that spine deficits in the DLPFC may contribute to subcortical hyperdopaminergia in schizophrenia.
authors: From the Departments of Neuroscience and Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh.
authors: Dibyadeep
authors: D
authors: Datta
authors: From the Departments of Neuroscience and Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh.
authors: Dominique
authors: D
authors: Arion
authors: From the Departments of Neuroscience and Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh.
authors: Kaitlyn M
authors: KM
authors: Roman
authors: From the Departments of Neuroscience and Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh.
authors: David W
authors: DW
authors: Volk
authors: From the Departments of Neuroscience and Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh.
authors: David A
authors: DA
authors: Lewis
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics*; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism*; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D051376:Actin-Related Protein 2-3 Complex