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Cited by 101Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental Disorders

Altered Cortical CDC42 Signaling Pathways in Schizophrenia: Implications for Dendritic Spine Deficits

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Ide, Masayuki, Lewis, David A.·2010·Biological Psychiatry
DOI 10.1016/j.biopsych.2010.02.016PMC PMC2900524
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Abstract

Background Spine density on the basilar dendrites of pyramidal neurons is lower in layer 3, but not in layers 5 and 6, in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. The expression of CDC42 (cell division cycle 42), a RhoGTPase that regulates the outgrowth of the actin cytoskeleton and promotes spine formation, is also lower in schizophrenia; however, CDC42 mRNA is lower across layers 3-6, suggesting that other lamina-specific molecular alterations are critical for the spine deficits in the illness. The CDC42 effector proteins 3 and 4 (CDC42EP3, CDC42EP4) are preferentially expressed in DLPFC layers 2 and 3, and CDC42EP3 appears to assemble septin filaments in spine necks. Therefore, alterations in CDC42EP3 could contribute to the lamina-specific spine deficits in schizophrenia. Methods We measured transcript levels of CDC42, CDC42EP3, CDC42EP4; their interacting proteins (septins [SEPT2, 3, 5, 6, 7, 8, and 11], anillin), and other spine-specific proteins (spinophilin, PSD-95, and synaptopodin) in the DLPFC from 31 subjects with schizophrenia and matched normal comparison subjects. Results The expression of CDC42EP3 mRNA was significantly increased by 19.7%, and SEPT7 mRNA was significantly decreased by 6.9% in subjects with schizophrenia. Cortical levels of CDC42EP3 and SEPT7 mRNAs were not altered in monkeys chronically exposed to antipsychotic medications. Conclusions Activated CDC42 is thought to disrupt septin filaments transiently in spine necks, allowing the molecular translocations required for synaptic potentiation. Thus, altered CDC42 signaling via CDC42EP3 may perturb synaptic plasticity and contribute to the spine deficits observed in layer 3 pyramidal neurons in schizophrenia.

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  • Increased expression of the CDC42 effector protein CDC42EP3 occurs specifically in layer III in the dlPFC of schizophrenia patients.

    “A later study found increased expression of the CDC42 effector protein CDC42EP3 specifically in layer III, as well as reduced septin-7 (SEPT7), suggesting altered regulation of septin filaments in layer III synapses135.”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [135]

    The Results report increased CDC42EP3 mRNA in the DLPFC of subjects with schizophrenia, but do not establish that the increase occurs specifically in layer III. The Discussion says CDC42EP3 is preferentially expressed in layers 2–3 and explicitly allows that its increase might occur in layers 5–6. The study measured mRNA, not CDC42EP3 protein. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Reduced septin-7 (SEPT7) occurs in the dlPFC of schizophrenia patients.

    “A later study found increased expression of the CDC42 effector protein CDC42EP3 specifically in layer III, as well as reduced septin-7 (SEPT7), suggesting altered regulation of septin filaments in layer III synapses135.”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [135]

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Authors
Ide, M., & Lewis, D. A.
Affiliations
University of Pittsburgh (US)
Corresponding author
Lewis, David A.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2010-07
Volume
68
Issue
1
Pages
25-32
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2010.02.016
PMC
PMC2900524
OpenAlex
W2004451728
Cited by
101
References
3
Citations by year
2026: 3 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 8 · 2021: 7 · 2020: 3 · 2019: 5 · 2018: 6 · 2017: 4 · 2016: 11 · 2015: 8 · 2014: 5 · 2013: 7 · 2012: 6
FWCI
6.12
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (MH043784, MH084053)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
schizophrenia, dendritic spines, Cdc42, septins, SEPT7, dorsolateral prefrontal cortex, synaptic plasticity, actin cytoskeleton, spinophilin, PSD-95, anillin
MeSH terms
Disks Large Homolog 4 Protein, Neurabins, Adult, Analysis of Variance, Animals, Contractile Proteins, Cytoskeletal Proteins, Female, Gene Expression Regulation, Humans, Macaca fascicularis, Male, Membrane Proteins, Microfilament Proteins, Middle Aged, Nerve Tissue Proteins, RNA, Messenger, Schizophrenia, Antipsychotic Agents, Signal Transduction, Case-Control Studies, Synaptophysin, Prefrontal Cortex, Pyramidal Cells, GTP-Binding Protein Regulators, cdc42 GTP-Binding Protein, Intracellular Signaling Peptides and Proteins, Dendritic Spines

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