Presentation_1_Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice.pptx

Background: Gamma-aminobutyric acid (GABA) type A receptors are positively allosterically modulated by benzodiazepine binding, leading to a potentiated response to GABA. Diazepam (DZP, a benzodiazepine) is widely prescribed for anxiety, epileptic discharge, and insomnia, and is also used as a muscle relaxant and anti-convulsant. However, some adverse effects – such as tolerance, dependence, withdrawal effects, and impairments in cognition and learning – are elicited by the long-term use of DZP. Clinical studies have reported that chronic DZP treatment increases the risk of dementia in older adults. Furthermore, several studies have reported that chronic DZP administration may affect neuronal activity in the hippocampus, dendritic spine structure, and cognitive performance. However, the effects of chronic DZP administration on cognitive function in aged mice is not yet completely understood. Methods: A behavioral test, immunohistochemical analysis of neurogenic and apoptotic markers, dendritic spine density analysis, and long-term potentiation (LTP) assay of the hippocampal CA1 and CA3 were performed in both young (8 weeks old) and middle-aged (12 months old) mice to investigate the effects of chronic DZP administration on cognitive function. The chronic intraperitoneal administration of DZP was performed by implanting an osmotic minipump. To assess spatial learning and memory ability, the Morris water maze test was performed. Dendritic spines were visualized using Lucifer yellow injection into the soma of hippocampal neurons, and spine density was analyzed. Moreover, the effects of exercise on DZP-induced changes in spine density and LTP in the hippocampus were assessed. Results: Learning performance was impaired by chronic DZP administration in middle-aged mice but not in young mice. LTP was attenuated by DZP administration in the CA1 of young mice and the CA3 of middle-aged mice. The spine density of hippocampal neurons was decreased by chronic DZP administration in the CA1 of both young and middle-aged mice ...