Long-Term Effects of Juvenile Fluoxetine Exposure on Autophagy Induction and Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Male Mice
Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer’s disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. Because AD is characterized by the pathological accumulation of hyperphosphorylated Tau – which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), this thesis evaluated the potential long-term effects of adolescent FLX exposure on these pathways, using mice as a model system. Specifically, C57BL/6 adolescent male mice were administered FLX (20 mg/kg/day) during adolescence (postnatal days [PD] 35-49). After a 21-day washout period, mice were euthanized (PD70) and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated Tau, within the hippocampus and prefrontal cortex. We found that FLX exposure altered protein expression of autophagy and UPS markers in both the hippocampus and prefrontal cortex. Specifically, that juvenile FLX exposure facilitated autophagy activation mostly in the adult prefrontal cortex (increased LC3-II and decreased p62). Lastly, while K48-pUb was not affected, antidepressant history mediated a long-lasting increase of phosphorylated Tau in both brain regions assessed, suggesting that exposure to FLX during adolescence may increase the expression of neurodegenerative markers in adulthood.
Rodriguez, Minerva, "Long-Term Effects of Juvenile Fluoxetine Exposure on Autophagy Induction and Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Male Mice" (2022). ETD Collection for University of Texas, El Paso. AAI29206852.