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.

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    • "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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    ABSTRACT: Fragile X mental retardation protein (FMRP) is an RNA binding protein with 842 target mRNAs in mammalian brain. Silencing of the fragile X mental retardation 1 (FMR1) gene leads to loss of expression of FMRP and upregulated metabotropic glutamate receptor 5 (mGluR5) signaling resulting in the multiple physical and cognitive deficits associated with fragile X syndrome (FXS). Reduced FMRP expression has been identified in subjects with autism, schizophrenia, bipolar disorder, and major depression who do not carry the mutation for FMR1. Our laboratory has recently demonstrated altered expression of four downstream targets of FMRP-mGluR5 signaling in brains of subjects with autism: homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP). In the current study we investigated the expression of the same four proteins in lateral cerebella of subjects with schizophrenia, bipolar disorder, and major depression and in frontal cortex of subjects with schizophrenia and bipolar disorder. In frontal cortex we observed: 1) reduced expression of 120kDa form of APP in subjects with schizophrenia and bipolar disorder; 2) reduced expression of 61kDa and 33kDa forms of STEP in subjects with schizophrenia; 3) reduced expression of 88kDa form of APP in subjects with bipolar disorder; and 3) trends for reduced expression of 88kDa form of APP and homer 1 in subjects with schizophrenia and bipolar disorder, respectively. In lateral cerebella there was no group difference, however we observed increased expression of RAC1 in subjects with bipolar disorder, and trends for increased RAC1 in subjects with schizophrenia and major depression. Our results provide further evidence that proteins involved in the FMRP-mGluR5 signaling pathway are altered in schizophrenia and mood disorders. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 05/2015; 165(2-3). DOI:10.1016/j.schres.2015.04.012 · 3.92 Impact Factor
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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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    ABSTRACT: The GABA transmitter system plays a vital role in modulating synaptic formation and activity during development. The GABAB receptor subtype in particular has been implicated in cell migration, promotion of neuronal differentiation, neurite outgrowth, and synapse formation but it's role in development is not well characterized. In order to investigate the effects of brief alterations in GABAB signaling in development, we administered to rats the GABAB agonist baclofen (2.0 mg/kg) or antagonist phaclofen (0.3 mg/kg) on postnatal days 7, 9, and 12, and evaluated sensorimotor gating in adulthood. We also examined tissue for changes in multiple proteins associated with GABAB receptor function and proteins associated with synapse formation. Our data indicate that early postnatal alterations to GABAB receptor-mediated signaling produced sex differences in sensorimotor gating in adulthood. Additionally, we found differences in GABAB receptor subunits and kalirin protein levels in the brain versus saline treated controls. Our data demonstrate that a subtle alteration in GABAB receptor function in early postnatal life induces changes that persist into adulthood.
    International Journal of Developmental Neuroscience 10/2014; 41. DOI:10.1016/j.ijdevneu.2014.10.001 · 2.58 Impact Factor
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    • "Intriguingly, overexpression of kalirin-7 does not only increase the branching of dendrites of hippocampal CA1 interneurons, but induces also the formation of spine-like structures in these usually aspiny cells (Ma et al., 2008), indicating a role of this Rac GEF in potentiating the formation of excitatory postsynaptic terminals in GABAergic neurons. Interestingly, kalirin-7, NRG1, and ErbB4 are highly and specifically expressed in GABAergic interneurons, and have been associated with schizophrenia (Ma et al., 2001, 2005; Hill et al., 2006; Li et al., 2006; Fazzari et al., 2010; Del Pino et al., 2013; Kasnauskiene et al., 2013). Since the dendritic length of interneurons is reduced in schizophrenia (Kalus et al., 2002), understanding how NRG1/ErbB4 signaling regulates the dendrites of these cells may help clarifying the mechanisms underlying the cortical defects in this disorder. "
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    ABSTRACT: Rac GTPases are regulators of the cytoskeleton that play an important role in several aspects of neuronal and brain development. Two distinct Rac GTPases are expressed in the developing nervous system, the widely expressed Rac1 and the neural-specific Rac3 proteins. Recent experimental evidence supports a central role of these two Rac proteins in the development of inhibitory GABAergic interneurons, important modulatory elements of the brain circuitry. The combined inactivation of the genes for the two Rac proteins has profound effects on distinct aspects of interneuron development, and has highlighted a synergistic contribution of the two proteins to the postmitotic maturation of specific populations of cortical and hippocampal interneurons. Rac function is modulated by different types of regulators, and can influence the activity of specific effectors. Some of these proteins have been associated to the development and maturation of interneurons. Cortical interneuron dysfunction is implicated in several neurological and psychiatric diseases characterized by cognitive impairment. Therefore the description of the cellular processes regulated by the Rac GTPases, and the identification of the molecular networks underlying these processes during interneuron development is relevant to the understanding of the role of GABAergic interneurons in cognitive functions.
    Frontiers in Cellular Neuroscience 09/2014; 8:307. DOI:10.3389/fncel.2014.00307 · 4.29 Impact Factor
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