Neuropathology of the cerebral cortex observed in a range of animal models of prenatal cocaine exposure may reflect alterations in genes involved in the Wnt and cadherin systems

Novikova, Svetlana I.; He, Fang; Bai, Jie; Lidow, Michael S.

doi:10.1002/syn.20134

Cited by 24 publications

(19 citation statements)

References 99 publications

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“…Consistently, mutations of Derailed, a Drosophila Wnt receptor (13), cause memory deficits in Drosophila (37,38). Recent studies suggest that aberrant Wnt signaling is implicated in multiple abnormal brain conditions, including Alzheimer disease (34,50), schizophrenia (22,51,52), and drug abuse (35). Our findings of the role of Wnt signaling in synaptic plasticity provide a new perspective for understanding the etiologic mechanism for these mental disorders.…”

Section: Discussionmentioning

confidence: 53%

Activity-dependent Synaptic Wnt Release Regulates Hippocampal Long Term Potentiation

Chen

Park

Tang

2006

Journal of Biological Chemistry

274

285

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Wnts are important for various developmental and oncogenic processes. Here we show that Wnt signaling functions at synapses in hippocampal neurons. Tetanic stimulations induce N-methyl-Daspartate receptor-dependent synaptic Wnt3a release, nuclear ␤-catenin accumulations, and the activation of Wnt target genes. Suppression of Wnt signaling impairs long term potentiation. Conversely, activation of Wnt signaling facilitates long term potentiation. These findings suggest that Wnt signaling plays a critical role in regulating synaptic plasticity.Wnts are a family of secreted, lipid-modified signaling proteins that act as short range ligands to locally activate receptor-mediated signaling cascades. Wnt signaling is critical for a variety of developmental processes; its dysregulation is the causal factor for many diseases, especially cancer (1, 2). Wnt ligands bind to Frizzled receptors to activate intracellular signaling cascades, including the Wnt/␤-catenin, Wnt/Ca 2ϩ , and Wnt/planar cell polarity pathways (3). In the canonical Wnt/␤-catenin-signaling pathway, Frizzled receptors signal through Dishevelled to inhibit the kinase activity of glycogen synthase kinase 3␤ in a protein degradation complex containing Axin, ␤-catenin, and other proteins. When Wnt signaling is inactive, ␤-catenin is phosphorylated by glycogen synthase kinase 3␤ and thus rapidly degraded via the proteosome pathway; the activation of Wnt signaling stabilizes ␤-catenin by inhibiting glycogen synthase kinase 3␤. Stabilized ␤-catenin translocates to the nuclei and binds the TCF/LEF family of transcription factors to regulate the expression of Wnt target genes (1, 2). In addition, ␤-catenin is a component of the cadherin complex and plays an important role in regulating cell-cell adhesion (4). Among many Wnt-regulated developmental processes are neural patterning and differentiation (5), including hippocampal formation (6 -8), dendritic morphogenesis (9, 10), axon guidance (11-16), and synapse formation (11,17,18).Wnts are expressed in the brain (19 -21). Dysregulation of Wnt signaling has been suggested as an etiological cause for specific mental disorders. For example, Wnt signaling is up-regulated in schizophrenic brains (22)(23)(24). Several studies suggested an association of Frizzled-3 with schizophrenic susceptibility (25-27). On the other hand, downregulation of the Wnt/␤-catenin pathway is implicated in Alzheimer disease etiology (28 -34). A recent study indicated that cocaine exposures affect the expression of many Wnt signal-related genes (35). In addition, mutation of Dishevelled-1 in mice produces behavioral impairments (36), whereas mutation of a Drosophila Wnt receptor, Derailed (13), causes memory deficits (37, 38). Collectively, available data point to the role of Wnt signaling in the modulation of brain functions. However, the mechanism by which Wnt signaling regulates brain function is completely unknown.Here we report the synaptic localization of Wnt signaling proteins in mouse hippocampal neurons, the activity-induced Wnt3a rel...

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Section: Discussionmentioning

confidence: 53%

Activity-dependent Synaptic Wnt Release Regulates Hippocampal Long Term Potentiation

Chen

Park

Tang

2006

Journal of Biological Chemistry

274

285

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“…Beta catenin is another gene that has been routinely reported in microarray studies as regulated by cocaine (i.e., Freeman et al 2001a;Zhang et al 2002;Novikova et al 2005) and recent work suggests that the D1 receptor is a critical mediator for cocaine-induced expression of this gene (Zhang et al 2002). Other genes identified here that have been previously shown to be involved in cocaine reward/regulated by cocaine include, Hivep2 (Reynolds et al 2006), Rxrb (Krezel et al 1998), and Chgb (Che et al 2006).…”

Section: Cocaine-responsive Gene Expression Of Non-circadian Genesmentioning

confidence: 63%

Gene profiling the response to repeated cocaine self-administration in dorsal striatum: A focus on circadian genes

et al. 2008

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Alterations in gene expression in the dorsal striatum caused by chronic cocaine exposure have been implicated in the long-term behavioral changes associated with cocaine addiction. To gain further insight into the molecular alterations that occur as a result of cocaine self-administration, we conducted a microarray analysis of gene expression followed by bioinformatic gene network analysis that allowed us to identify adaptations at the level of gene expression as well as into interconnected networks. Changes in gene expression were examined in the dorsal striatum of rats 1 day after they had self-administered cocaine for 7 days under a 24-hr access, discrete trial paradigm (averaging 98 mg/kg/day). Here we report the regulation of the circadian genes Clock, Bmal1, Cryptochrome1, Period2, as well as several genes that are regulated by/associated with the circadian system (i.e., early growth response 1, dynorphin). We also observed regulation of other relevant genes (i.e., Nur77, beta catenin). These changes were then linked to curated pathways and formulated networks which identified circadian rhythm processes as affected by cocaine self-administration. These data strongly suggest involvement of circadian-associated genes in the brain's response to cocaine and may contribute to an understanding of addictive behavior including disruptions in sleep and circadian rhythmicity. Classification Molecular Brain Research SectionDisease-Related Neuroscience

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“…The mechanisms involved in the adverse developmental effects of cocaine are, however, not fully known. Novikova and coworkers identified Wnt/cadherin and multiple apoptosis-signaling pathways as being involved in cocaine’s actions on brain development from gene expression profiling of the cortex of cocaine-treated mouse fetuses (Novikova et al, 2005a, 2005b). Nonetheless, the cell type or types and cell-type specific gene alterations related to developmental effects of cocaine are unknown.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Reveals Distinct Cocaine-Responsive Genes in Human Fetal CNS Cell Types

Lee

Lehrmann

Hayashi³

et al. 2009

Journal of Addiction Medicine

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Objectives-Prenatal exposure to cocaine causes cytoarchitectural alterations in the developing neocortex. Previously, we reported that cocaine inhibits neural progenitor cell proliferation through oxidative endoplasmic reticulum stress and consequent down-regulation of cyclin A, whereas cyclin A expression was increased in astrocytes. In the present study, cell type-specific responses to cocaine were further explored.Methods-Gene expression profiles were examined in five types of cells obtained from the human fetal cerebral cortex at 20 weeks gestation. Cells were treated with 100 µM cocaine in vitro for 24 hr, followed by gene expression analysis using a human neural/stem cell/drug abuse-focused cDNA array, with verification by quantitative real-time RT-PCR.Results-Cocaine influenced transcription of distinct categories of genes in a cell type-specific manner. Cocaine down-regulated cytoskeleton-related genes including ezrin, γ2 actin, α3d tubulin and α8 tubulin in neural and/or A2B5+ progenitor cells. In contrast, cocaine modulated immune and cell death-related genes in microglia and astrocytes. In microglia, cocaine up-regulated the immunoregulatory and pro-apoptotic genes IL-1β and BAX. In astrocytes, cocaine down-regulated the immune response gene glucocorticoid receptor and up-regulated the anti-apoptotic genes 14-3-3 ε and HVEM. Therefore, cell types comprising the developing neocortex show differential responses to cocaine.Conclusions-These data suggest that cocaine causes cytoskeletal abnormalities leading to disturbances in neural differentiation and migration in progenitor cells, while altering immune and apoptotic responses in glia. Understanding the mechanisms of cocaine's effects on human CNS cells may help in the development of therapeutic strategies to prevent or ameliorate cocaine-induced impairments in fetal brain development. Keywordscocaine; microarray; gene expression profiling; human fetal CNS cells; brain development Understanding the mechanisms through which cocaine causes adverse effects on the developing brain has received considerable attention, because several hundred thousand fetuses Send correspondence and reprint requests to Dr. Chun-Ting Lee, NIDA Intramural Research Program, 333 Cassell Drive, Triad Bldg, Room 3505, Baltimore, MD, 21224, Tel.: 443-740-2604; Fax: 443-740-2123, email: clee@mail.nih per year are exposed to cocaine in the United States alone (Singer et al., 2002). Clinical studies have correlated neocortical architecture modifications and behavioral disturbances with in utero cocaine exposure (Chiriboga et al., 1999;Bellini et al., 2000;Singer et al., 2008). In subhuman primates, administration of cocaine at the time of neocortical neurogenesis (the second trimester) disturbs development of cerebral cortex, causing reduced neocortex volume, disturbed lamination, altered positioning of cerebral cortical neurons, and reduced density and number of cortical neurons (Lidow, 1995;. Notably, these anatomical abnormalities result in neurobehavioral impairments in in...

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Neuropathology of the cerebral cortex observed in a range of animal models of prenatal cocaine exposure may reflect alterations in genes involved in the Wnt and cadherin systems

Cited by 24 publications

References 99 publications

Activity-dependent Synaptic Wnt Release Regulates Hippocampal Long Term Potentiation

Activity-dependent Synaptic Wnt Release Regulates Hippocampal Long Term Potentiation

Gene profiling the response to repeated cocaine self-administration in dorsal striatum: A focus on circadian genes

Gene Expression Profiling Reveals Distinct Cocaine-Responsive Genes in Human Fetal CNS Cell Types

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