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

Abstract

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.

Rapid modulation of spine morphology by the 5-HT 2A serotonin receptor through kalirin-7 signaling

“…Disruption of 5-HT 2A receptor signaling is implicated in several prevalent psychiatric disorders (6)(7)(8)(9)(10)(11), and the underlying effect of these alterations of serotonergic signaling may involve structural changes in synapses, which may alter neural circuits. Additionally, kalirin has reduced mRNA expression in the cortex of schizophrenia patients (42), and MUPP1 has been genetically associated with drug withdrawal seizures (43). Thus, the signaling pathway we describe here may be important in the pathogenesis of a number of psychiatric disorders.…”

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

“…35 Reduced expression of CDC42 has previously been shown in the dorsolateral prefrontal cortex of subjects with schizophrenia and this was correlated with decreased dendritic spine density in schizophrenia. 36 Incidentally, GSK3B (OMIM: 605004) which is also modulated by DISC-1, is part of the cell cycle pathway, although not directly contributing to susceptibility in this study. 37 The third pathway identified in all three samples involved carbohydrate structures attached to glycolipids, glycoproteins and proteoglycans.…”

Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia

“…Reduced mRNA expression of cell division cycle 42, which promotes dendritic spine outgrowth (Irie and Yamaguchi, 2002), and Kalirin 7, which is necessary for both spine outgrowth and mediates LTP-induced spine structural plasticity (Penzes et al, 2001), was found in PFC, and correlated with reductions in spine density (Hill et al, 2006). Of interest, spinophilin has been recently shown to be a mediator of LTD-, but not LTPinduced structural plasticity (Feng et al, 2000).…”