1Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Jan 40: 1-11
TitleTwo-dimensional gel electrophoresis revealed antipsychotic drugs induced protein expression modulations in C6 glioma cells.
AbstractThe efficacy and side effects of long-term administration of antipsychotic drugs (APDs) may be attributed to drug-induced change in protein expression in brain cells. Glial cells are non-neuronal cells that can provide nutrients and physiological support to neuronal cells. Glial cells are believed to participate in neurotransmission, neurons' early development, and guiding migration of neurons. Accumulated clinical data also indicate relationships between disturbance of glial cells' function and various psychotic diseases including schizophrenia. We used two-dimensional gel electrophoresis coupled with MALDI-TOF/TOF mass spectrometry protein identification to analyze differentially expressed proteins in haloperidol-, risperidone-, and clozapine-treated C6 glioma cells. We found that the expression of pericentrin, glial fibrillary acidic protein, Rho GDP-dissociation inhibitor 1, anionic trypsin-1, peroxiredoxin-1, and parvalbumin were regulated by each of the three APDs. Western blot analysis supported the findings. Real-time quantitative PCR detected changed transcriptions of those proteins. Protein and gene expression of N-cadherin in C6 cells were affected by haloperidol and clozapine but not risperidone. In addition, regulatory effects of clozapine on the glyceraldehyde 3-phosphate dehydrogenase gene were observed in C6 cells. This may be the first study to uncover how APD-modulated genes may cause protein expression changes and affect ARHGDIA-mediated regulation of Rho GTPase family proteins in glial cells.
SCZ Keywordsschizophrenia
2Biol. Psychiatry 2015 Dec 78: 775-85
TitleAltered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia.
AbstractCognitive 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.
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.
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.
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.
SCZ Keywordsschizophrenia