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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 12; pp. 5069 - 5074
• Main Authors: Noel, Melissa, Norris, Erin H, Strickland, Sidney
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.03.2011; National Acad Sciences
• Subjects: adulthood; adults; Animals; Apoptosis; Behavior, Animal - drug effects; Biological Sciences; Brain; Caspase 3 - genetics; Caspase 3 - metabolism; caspase-3; cell death; Central Nervous System Depressants - adverse effects; Central Nervous System Depressants - pharmacology; central nervous system diseases; cognition; Cognition Disorders - chemically induced; Cognition Disorders - metabolism; death; Ethanol; Ethanol - adverse effects; Ethanol - pharmacology; fearfulness; Female; Fetal Alcohol Spectrum Disorders - genetics; Fetal Alcohol Spectrum Disorders - metabolism; Fetal alcohol syndrome; fetal development; Forebrain; Genotypes; Hippocampus; Humans; Male; mental health; Mice; Mice, Knockout; Neurodegeneration; neurodegenerative diseases; neurons; Neurotoxicity; Physiological regulation; Plasminogen activators; Pregnancy; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; synaptogenesis; t-plasminogen activator; Thalamus; Tissue Plasminogen Activator - genetics; Tissue Plasminogen Activator - metabolism; Tissues
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1017608108

Ethanol exposure during developmental synaptogenesis can lead to brain defects referred to as fetal alcohol syndrome (FAS), which can include mental health problems such as cognitive deficits and mental retardation. In FAS, widespread neuronal death and brain mass loss precedes behavioral and cognitive impairments in adulthood. Because tissue plasminogen activator (tPA) has been implicated in neurodegeneration, we examined whether it mediates FAS. Neonatal WT and tPA⁻/⁻ mice were injected with ethanol to mimic FAS in humans. In WT mice, ethanol elicited caspase-3 activation, significant forebrain neurodegeneration, and decreased contextual fear conditioning in adults. However, tPA-deficient mice were protected from these neurotoxicities, and this protection could be abrogated by exogenous tPA. Selective pharmacological modulators of NMDA and GABAA receptor pathways revealed that the effects of tPA were mediated by the NR2B subunit of the NMDA receptor. This study identifies tPA as a critical signaling component in FAS.