|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. As shown in the figure,
expression levels of each mRNA were reduced in a schizophrenia subject compared
to a matched control. Quantitative studies confirmed reduced expression
of each of these mRNAs 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= .007) and Cdc42 (r = 0.71, p = .009) mRNAs. In
contrast, the expression levels of Cdc42 and Duo mRNAs were not altered
in monkeys chronically exposed to the antipsychotic medications haloperidol
or olanzapine. 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.