👤 Tanner McVey

Children who experience cardiac arrest often suffer lasting neurological deficits, including impairments to learning and memory, due to global cerebral ischemia (GCI). Using a juvenile mouse model of cardiac arrest and resuscitation, we investigated the long-term effects of GCI and potential therapeutic interventions. Following juvenile GCI, long-term potentiation (LTP) and memory were impaired for several weeks followed by endogenous recovery coinciding with changes in brain-derived neurotrophic factor (BDNF) levels, an essential regulator of synaptic plasticity specifically in juveniles but not adults. Given that BDNF is unstable in plasma and cannot cross the blood-brain barrier, we explored the use of type II ampakines, positive allosteric modulators of AMPA receptors, to increase BDNF protein levels in the brain. In vivo administration of type II ampakines 14 days after GCI increased hippocampal BDNF levels, restored LTP, and improved hippocampal-dependent memory and learning behavior. These findings highlight the potential of type II ampakines as an innovative therapeutic intervention to restore synaptic and cognitive function at delayed time points after juvenile GCI. Show less

Global cerebral ischemia (GCI) during childhood is a leading cause of long-term cognitive impairment, yet no therapies currently exist to promote recovery in survivors. We previously demonstrated that juvenile mice exhibit transient hippocampal synaptic dysfunction after GCI, associated with reduced brain-derived neurotrophic factor (BDNF) expression and partial endogenous recovery over time. In this study, we tested whether delayed treatment with fluoxetine (FLX)-a selective serotonin reuptake inhibitor (SSRI) known to enhance BDNF-TrkB signaling-could accelerate synaptic recovery. Juvenile mice underwent cardiac arrest and cardiopulmonary resuscitation, followed by in vivo FLX or vehicle administration from postinjury days 10-13. Electrophysiological recordings on day 14 revealed that FLX restored hippocampal long-term potentiation (LTP) in males but not females. This effect was paralleled by an increase in hippocampal BDNF expression in FLX-treated males, whereas no change was observed in females. Paired ex vivo experiments further confirmed that acute FLX exposure rescued LTP in GCI-injured male slices. These findings suggest that FLX promotes synaptic recovery through BDNF-TrkB signaling in males, while recovery in females may proceed via alternate, hormone-dependent mechanisms. Together, these results identify a novel therapeutic window for enhancing neuroplasticity after juvenile GCI and underscore the importance of developmental stage and biological sex in shaping responses to treatment. Show less