Fate Analysis of Adult Hippocampal Progenitors in a Murine Model of Fetal Alcohol Spectrum Disorder (FASD)

Kajimoto, Kan; Allan, Andrea M.; Cunningham, Lee Anna

doi:10.1371/journal.pone.0073788

Cited by 24 publications

(46 citation statements)

References 73 publications

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“…While not a part of the present study, previous work with our PAE model has found deficits in neurogenesis [47] increased depressive behavior [48] and learning deficits [36]. Although the existing literature suggests that CDK5 and GSK3β contribute to behavioral and cognitive functioning, their roles in PAE-associated impairments in these processes are unknown.…”

Section: Discussionmentioning

confidence: 69%

Prenatal alcohol exposure alters p35, CDK5 and GSK3β in the medial frontal cortex and hippocampus of adolescent mice

2014

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Fetal alcohol spectrum disorders (FASDs) are the number one cause of preventable mental retardation. An estimated 2-5% of children are diagnosed as having a FASD. While it is known that children prenatally exposed to alcohol experience cognitive deficits and a higher incidence of psychiatric illness later in life, the pathways underlying these abnormalities remain uncertain. GSK3β and CDK5 are protein kinases that are converging points for a vast number of signaling cascades, including those controlling cellular processes critical to learning and memory. We investigated whether levels of GSK3β and CDK5 are affected by moderate prenatal alcohol exposure (PAE), specifically in the hippocampus and medial frontal cortex of the adolescent mouse. In the present work we utilized immunoblotting techniques to demonstrate that moderate PAE increased hippocampal p35 and β-catenin, and decreased total levels of GSK3β, while increasing GSK3β Ser9 and Tyr216 phosphorylation. Interestingly, different alterations were seen in the medial frontal cortex where p35 and CDK5 were decreased and increased total GSK3β was accompanied by reduced Tyr216 of the enzyme. These results suggest that kinase dysregulation during adolescence might be an important contributing factor to the effects of PAE on hippocampal and medial frontal cortical functioning; and by extension, that global modulation of these kinases may produce differing effects depending on brain region.

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Section: Discussionmentioning

confidence: 69%

Prenatal alcohol exposure alters p35, CDK5 and GSK3β in the medial frontal cortex and hippocampus of adolescent mice

2014

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“…In a similar drinking model of PAE using 10% ( w / v ) ad libitum, with exposure from GD0 to 19 as a low-moderate BAC paradigm study, PAE mice did not respond to an enriched environment with enhanced neuronal progenitor survival or differentiation in the subgranular zone of the dentate gyrus (Choi et al 2005). In a follow-up study using the same PAE paradigm but limiting alcohol exposure to 4 h per day, it was shown that post-mitotic neurons from PAE mice housed in an enriched environment are not capable of survival in the dentate gyrus (Kajimoto et al 2013). Moreover, the neurogenesis deficit was associated with impaired spatial pattern recognition and caused by dentate gyrus-mediated neuronal (learning) impairments in these PAE mice (Kajimoto et al 2013).…”

Section: Mouse Models Of Prenatal Alcohol Exposurementioning

confidence: 99%

“…In a follow-up study using the same PAE paradigm but limiting alcohol exposure to 4 h per day, it was shown that post-mitotic neurons from PAE mice housed in an enriched environment are not capable of survival in the dentate gyrus (Kajimoto et al 2013). Moreover, the neurogenesis deficit was associated with impaired spatial pattern recognition and caused by dentate gyrus-mediated neuronal (learning) impairments in these PAE mice (Kajimoto et al 2013). Thus, while dosage of alcohol in the PAE mouse paradigms discussed might vary, it appears that there are changes in brain morphology and cellular differentiation at any dosage of alcohol exposure, although some cell types are more resilient than others.…”

Section: Mouse Models Of Prenatal Alcohol Exposurementioning

confidence: 99%

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

Petrelli

Weinberg

Hicks

2018

Biochem. Cell Biol.

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The potential impact of prenatal alcohol exposure (PAE) varies considerably among exposed individuals, with some displaying serious alcohol-related effects and many others showing few or no overt signs of fetal alcohol spectrum disorder (FASD). In animal models, variables such as nutrition, genetic background, health, other drugs, and stress, as well as dosage, duration, and gestational timing of exposure to alcohol can all be controlled in a way that is not possible in a clinical situation. In this review we examine mouse models of PAE and focus on those with demonstrated craniofacial malformations, abnormal brain development, or behavioral phenotypes that may be considered FASD-like outcomes. Analysis of these data should provide a valuable tool for researchers wishing to choose the PAE model best suited to their research questions or to investigate established PAE models for FASD comorbidities. It should also allow recognition of patterns linking gestational timing, dosage, and duration of PAE, such as recognizing that binge alcohol exposure(s) during early gestation can lead to severe FASD outcomes. Identified patterns could be particularly insightful and lead to a better understanding of the molecular mechanisms underlying FASD.

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“…This “drinking in the dark” model results in blood alcohol content of 20 mM 4 h after consumption, similar to slightly more than one drink per day (Valenzuela, Morton, Diaz, & Topper, 2012); dams consume alcohol chronically, during preconception and gestation up to embryonic (E) days 15–17. Neurogenesis was chosen as a mechanism for investigation based on our previous publications demonstrating that alcohol elicits long-lasting effects seen in adulthood on neural progenitor cells (NPC) left over from development, including alterations in cell fate (Kajimoto, Allan, & Cunningham, 2013) and the neurogenic capacity to respond to environmental cues (Choi, Allan, & Cunningham, 2005). Ex vivo proliferating and differentiated cell cultures comprised of NPC from E15–E17 tissue exposed to alcohol in vivo were used for transcriptome analysis of neurogenesis-related genes.…”

Section: Introductionmentioning

confidence: 99%

Prenatal alcohol exposure alters expression of neurogenesis-related genes in an ex vivo cell culture model

Tyler

Allan

2014

Alcohol

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Prenatal alcohol exposure can lead to long-lasting changes in functional and genetic programs of the brain, which may underlie behavioral alterations seen in Fetal Alcohol Spectrum Disorder (FASD). Aberrant fetal programming during gestational alcohol exposure is a possible mechanism by which alcohol imparts teratogenic effects on the brain; however, current methods used to investigate the effects of alcohol on development often rely on either direct application of alcohol in vitro or acute high doses in vivo. In this study, we used our established moderate prenatal alcohol exposure (PAE) model, resulting in maternal blood alcohol content of approximately 20 mM, and subsequent ex vivo cell culture to assess expression of genes related to neurogenesis. Proliferating and differentiating neural progenitor cell culture conditions were established from telencephalic tissue derived from embryonic day (E) 15–17 tissue exposed to alcohol via maternal drinking throughout pregnancy. Gene expression analysis on mRNA derived in vitro was performed using a microarray, and quantitative PCR was conducted for genes to validate the microarray. Student's t tests were performed for statistical comparison of each exposure under each culture condition using a 95% confidence interval. Eleven percent of genes on the array had significantly altered mRNA expression in the prenatal alcohol-exposed neural progenitor culture under proliferating conditions. These include reduced expression of Adora2a, Cxcl1, Dlg4, Hes1, Nptx1, and Vegfa and increased expression of Fgf13, Ndn, and Sox3; bioinformatics analysis indicated that these genes are involved in cell growth and proliferation. Decreased levels of Dnmt1 and Dnmt3a were also found under proliferating conditions. Under differentiating conditions, 7.3% of genes had decreased mRNA expression; these include Cdk5rap3, Gdnf, Hey2, Heyl, Pard6b, and Ptn, which are associated with survival and differentiation as indicated by bioinformatics analysis. This study is the first to use chronic low to moderate PAE, to more accurately reflect maternal alcohol consumption, and subsequent neural progenitor cell culture to demonstrate that PAE throughout gestation alters expression of genes involved in neural development and embryonic neurogenesis.

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Fate Analysis of Adult Hippocampal Progenitors in a Murine Model of Fetal Alcohol Spectrum Disorder (FASD)

Cited by 24 publications

References 73 publications

Prenatal alcohol exposure alters p35, CDK5 and GSK3β in the medial frontal cortex and hippocampus of adolescent mice

Prenatal alcohol exposure alters p35, CDK5 and GSK3β in the medial frontal cortex and hippocampus of adolescent mice

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

Prenatal alcohol exposure alters expression of neurogenesis-related genes in an ex vivo cell culture model

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