Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia

• Published in: Molecular psychiatry Vol. 11; no. 6; pp. 557 - 566
• Main Authors: Hill, J J, Hashimoto, T, Lewis, D A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2006; Nature Publishing Group
• Subjects: Adult; Adult and adolescent clinical studies; Animals; Antipsychotic Agents - pharmacology; Antipsychotics; Behavioral Sciences; Biological and medical sciences; Biological Psychology; cdc42 GTP-Binding Protein - drug effects; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cdc42 protein; Dendritic spines; Dendritic Spines - drug effects; Dendritic Spines - metabolism; Female; Gene expression; Gene Expression Profiling; Guanine Nucleotide Exchange Factors - drug effects; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Haloperidol; Haplorhini; Humans; Hybridization; Male; Matched-Pair Analysis; Medical sciences; Medicine; Medicine & Public Health; Mental disorders; Middle Aged; Molecular modelling; Neuropeptides - drug effects; Neuropeptides - genetics; Neuropeptides - metabolism; Neurosciences; Olanzapine; original-article; Pharmacotherapy; Prefrontal cortex; Prefrontal Cortex - cytology; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Psychotropic drugs; rac1 GTP-Binding Protein - drug effects; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rac1 protein; rho GTP-Binding Proteins - drug effects; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; RhoA protein; RNA, Messenger - analysis; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - metabolism; Substantia grisea; pyramidal neuron; drebrin; dendritic spine; schizophrenia; RhoGTPase; duo; Human; Central nervous system; Schizophrenia; Prefrontal cortex; Gene expression; Encephalon; Psychosis; Messenger RNA; Dendritic spine; Pyramidal neuron
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4001792

Postmortem studies have revealed reduced densities of dendritic spines in the dorsal lateral prefrontal cortex (DLPFC) of subjects with schizophrenia. However, the molecular mechanisms that might contribute to these alterations are unknown. Recent studies of the intracellular signals that regulate spine dynamics have identified members of the RhoGTPase family (e.g., Cdc42, Rac1, RhoA) as critical regulators of spine structure. In addition, Duo and drebrin are spine-specific proteins that are critical for spine maintenance and spine formation, respectively. In order to determine whether the mRNA expression levels of Cdc42, Rac1, RhoA, Duo or drebrin are altered in schizophrenia, tissue sections containing DLPFC area 9 from 15 matched pairs of subjects with schizophrenia and control subjects were processed for in situ hybridization. Expression levels of these mRNAs were also correlated with DLPFC spine density in a subset of the same subjects. In order to assess the potential influence of antipsychotic medications on the expression of these mRNAs, similar studies were conducted in monkeys chronically exposed to haloperidol or olanzapine. The expression of each of these mRNAs was lower in the gray matter of the subjects with schizophrenia compared to the control subjects, although only the reductions in Cdc42 and Duo remained significant after corrections for multiple comparisons. In addition, spine density was strongly correlated with the expression levels of both Duo ( r =0.73, P =0.007) and Cdc42 ( r =0.71, P =0.009) mRNAs. In contrast, the expression levels of Cdc42 and Duo mRNAs were not altered in monkeys chronically exposed to antipsychotic medications. In conclusion, reduced expression of Cdc42 and Duo mRNAs may represent molecular mechanisms that contribute to the decreased density of dendritic spines in the DLPFC of subjects with schizophrenia.