Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice

Noel, Melissa E.; Norris, Erin H.; Strickland, Sidney

doi:10.1073/pnas.1017608108

Cited by 42 publications

(42 citation statements)

References 37 publications

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“…Taken together, normal nNos activity appears to have a protective role, while nNos mutations worsen brain abnormalities and behavioral outcomes in the presence of PAE when compared with the PAE WT controls. Interestingly, gene mutations (loss of gene activity) in Bax and tPA (tissue plasminogen activator) protect the brain from alcohol exposure in mouse models of PAE (Young et al 2003; Noel et al 2011). …”

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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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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“…Learning impairment has been reported following exposure to substances of abuse including ethanol. Ethanol causes deficits in the learning of hippocampal-dependent tasks, and spares the learning of hippocampal-independent tasks [37,38], and impairs the acquisition of contextual fear conditioning [22,38,39] but not the consolidation of conditioning [22].…”

Section: Introductionmentioning

confidence: 99%

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

Sircar

Ishiwari²

2014

Journal of Drug and Alcohol Research

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γ-hydroxybutyric acid (GHB) causes retrograde amnesia in juveniles and young adults. Earlier, we have reported that in adolescent rat, GHB impairs the hidden platform task performance in the Morris water maze. In the present study, a classical fear conditioning paradigm was used to examine the effects of GHB on the acquisition of contextual conditioning, a hippocampus-dependent associative task, and cued tone conditioning, a hippocampus-independent task, in adolescent rats. Administration of GHB before the presentation of tone-shock pairings dose-dependently disrupted the acquisition of contextual conditioning with no effect on tone conditioning, when conditioned fear was measured 24 h later. Administering GHB prior to testing did not disrupt either contextual or tone conditioning. These results demonstrate that in the adolescent rat exposure to GHB preferentially disrupt hippocampal-dependent learning.

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“…Tpa can also directly interact with the NMDA receptor to induce apoptosis in the hippocampus, and alcohol can kill developing hippocampal neurons through this same mechanism. Homozygous mutation of the tpa gene ameliorates alcohol’s teratogenic effects by reducing alcohol-induced neurodegeneration in the hippocampus (Noel et al, 2011). Bax is a second gene whose mutation can ameliorate alcohol-induced pathology.…”

Section: Discussionmentioning

confidence: 99%

Importance of genetics in fetal alcohol effects: Null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits

et al. 2015

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The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS−/− mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS−/− mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS−/− mice and their wild type controls received alcohol (0.0, 2.2, or 4.4 mg/g) daily over postnatal days 4–9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose-related deficits in rotarod and balance beam performance in both nNOS−/− and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS−/− mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS−/− mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS−/− mice, but not in wild type. Thus, homozygous mutation of the nNOS gene increases vulnerability to alcohol-induced cerebellar dysfunction and neuronal loss. nNOS is the first gene identified whose mutation worsens alcohol-induced cerebellar behavioral deficits.

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Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice

Cited by 42 publications

References 37 publications

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

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

Systemic Administration of γ-Hydroxybutyric Acid in Adolescent Rat Impairs Contextual Fear Conditioning, But Not Cued Conditioning

Importance of genetics in fetal alcohol effects: Null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits

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