Abstract
7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a brain-derived neurotrophic factor (BDNF) mimetic to selectively activate the tropomyosin-related kinase B (TrkB) with high affinity. We have previously demonstrated that 7,8-DHF in vitro rescues long-term synaptic plasticity in the hippocampus of aged rats. The present study assessed the effectiveness of 7,8-DHF on age-related declines in fear memories and amygdalar synaptic plasticity. We found that Sprague Dawley male rats began to show significant deficits in the acquisition and retention of memories for contextual and cued fear conditioning, as well as the reduction of BDNF, TrkB, and phosphorylated TrkB at the age of 25 months. Therefore, rats at 24 months old received intraperitoneal administration of either 7,8-DHF (5 mg/kg, i.p.) or vehicle once daily for a consecutive 4 weeks. At the end of treatment period, cognitive performance, amygdalar synaptic plasticity, synaptogenesis, and the phosphorylation of several proteins crucial to synaptic plasticity were evaluated. The results show that chronic 7,8-DHF treatments significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased spine density and number in several brain regions that process fear memory including the amygdala, hippocampus, and prefrontal cortex, facilitated basolateral amygdalar synaptic plasticity, and in turn prevented performance in fear conditioning tasks from declining. Our results thus confirm a critical role for TrkB signaling activation by 7,8-DHF in preventing age-related declines in fear learning and memory and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in reversing age-related memory impairment.