Fluoro Jade B staining shows evidence of cortical degeneration after ethanol exposure in a mouse model of fetal alcohol syndrome.

In humans, ethanol (EtOH) exposure during the period of synaptogenesis can result in brain defects referred to as fetal alcohol syndrome (FAS). This disorder is characterized by hyperactivity, cognitive deficits, mental retardation, psychosis, depression, and schizophrenia. In rodents, a strong dose of EtOH (comparable to a binge-like episode in humans) during the same developmental stage leads to widespread neurodegeneration and subsequent impairments in cognitive tasks. Neurodegeneration is believed to occur from decreased neuronal activity, resulting in dysfunctional synaptogenesis. Work from the Strickland Laboratory has implicated tissue plasminogen activator (tPA) in EtOH withdrawal-induced seizures and neurodegeneration. In order to determine if tPA plays a role in FAS, members of the Strickland Lab followed an acute EtOH paradigm where 7-day old WT and tPA-/- mice were treated with EtOH or saline. Mice were sacrificed 24 hours post-treatment, and their brains were dissected, sectioned, and stained with Fluoro-Jade B, which labels dead and degenerating neurons. Results indicate EtOH treatment triggered massive neurodegeneration in the cerebral cortex and thalamus of WT mice. This effect was not found, however, in the tPA-/- mice. Members of the Strickland Laboratory also collected samples for in-gel zymography and saw a significant upregulation of tPA activity in the forebrain of WT mice 24 hours after EtOH treatment. Furthermore, EtOH treatment induced significant cleavage of caspase-3, a key executioner of apoptosis, 8 hours after treatment in WT mice but not in tPA-/- mice. Moreover, tPA-/- mice, but not WT, showed significant up-regulation of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) 24 hours after EtOH suggesting that these molecules may confer neuroprotection from EtOH damage in these mice. These data suggest that tPA is an important mediator of EtOH-induced neurodegeneration during early stages of brain development, and further studies and analysis by graduate student Melissa Noel and Sidney Strickland will determine if tPA-/- mice are also protected from the behavioral and cognit

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