Hill JJ, Hashimoto T, Lewis DA. Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia. Mol Psychiat 11: 557-566

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Molecular Psychiatry (Impact Factor: 14.5). 07/2006; 11(6):557-66. DOI: 10.1038/
Source: PubMed


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.

    • "Hill et al. (2006) reported on a significant decrease in RAC1 mRNA expression in white matter of prefrontal cortex in subjects with schizophrenia (Hill et al., 2006). However, these authors did not report on any change in RAC1 expression in PFC of monkeys treated chronically with either haloperidol or olanzapine (Table 5; Hill et al., 2006). Thus, it appears unlikely that our results with RAC1 are due to antipsychotic treatment. "
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    • "Kalirin has also been implicated in several developmental disorders (Hutsler and Zhang, 2010; Penzes and Remmers, 2012; Deo et al., 2012). For example, in schizophrenia, altered kalirin has been found in the brain (Hill et al., 2006; Sweet et al., 2008; Penzes and Remmers, 2012), and mutations of the kalirin gene have been found to induce changes relevant to schizophrenia in animal model systems (Ma et al., 2008; Cahill et al., 2009). "
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