Date of Award
fetal alcohol syndrome, ethanol, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA)
Ethanol exposure during synaptogenesis can result in brain and behavior neurotoxic defects referred to as fetal alcohol syndrome (FAS). Since tissue plasminogen activator (tPA) has been implicated in mediating excitotoxic neurodegeneration we subjected neonatal WT and tPA-/- to an acute ethanol paradigm that serves as a model of FAS. We observed persistent upregulation of tPA and extensive neurodegeneration after ethanol in the forebrain of WT. However, tPA-/- mice were protected from neuronal death, suggesting tPA mediates ethanol-induced neurodegeneration and FAS in mice. Commensurate with neuronal death, we observed ethanol-induced cognitive impairments in adult WT, but not tPA-/- mice. To understand how ethanol affects tPA we subjected mice to drugs that mimic the actions of ethanol in the brain. tPA-/- mice were protected from neurodegeneration after treatment with NMDA-R antagonist, but not after GABAA-agonist, suggesting tPA acts via an NMDA-R mediated mechanism. We also investigated the role of the tPA inhibitor plasminogen activator inhibitor-1 (PAI-1) in FAS. We observed PAI-1-/- mice were more vulnerable to ethanol-induced neurodegeneration than WT mice. In addition, we found that tPA-/-:PAI-1+/- mice treated with ethanol showed increased neurodegeneration than tPA-/- mice. These results suggest PAI-1 is involved in neuronal survival after ethanol. Finally, we explored the role of tPA in hippocampal synaptic plasticity after chronic stress. We restrained WT, tPA-/-, and PAI-1-/- mice for 21 days. We found chronic stress increased tPA activity in WT and PAI-1-/- mice. Stress greatly reduced PAI-1 below baseline levels in WT mice. These stress-induced changes in tPA activity and PAI-1 resulted in decreased contextual fear conditioning in WT and PAI-1-/- mice. Chronic stress did not affect contextual learning in the tPA-/- mice. These results suggest tPA is necessary for the synaptic plasticity cascade that causes cognitive deficits after chronic stress exposure.
Noel-Castro, Melissa, "Novel Roles for the Tissue Plasminogen Activator System in the Development of Fetal Alcohol Syndrome and the Regulation of Contextual Learning After Stress" (2009). Student Theses and Dissertations. 121.