Altered cortical CDC42 signaling pathways in schizophrenia: implications for dendritic spine deficits.
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.
Ide
Masayuki
M
Department of Psychiatry, University of Pittsburgh, Pennsylvania 15213, USA.
Lewis
David A
DA
D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D020555:GTP-Binding Protein Regulators / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099273:Neurabins
D014150:Antipsychotic Agents; D003285:Contractile Proteins; D003598:Cytoskeletal Proteins; D000076122:Disks Large Homolog 4 Protein; D020555:GTP-Binding Protein Regulators; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016708:Synaptophysin; D020764:cdc42 GTP-Binding Protein; D000099273:Neurabins; C484093:CDC42EP3 protein, human; C501444:DLG4 protein, human; C504260:SYNPR protein, human; C095886:anillin
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