# Delayed Fluoxetine Administration Restores Hippocampal Function in a Juvenile Global Cerebral Ischemia Mouse Model in a Sex‐Specific Manner

## TL;DR

Delayed fluoxetine treatment helps male mice recover from brain injury, but not females, highlighting sex-specific responses.

## Contribution

Identifies a novel therapeutic window for fluoxetine in juvenile cerebral ischemia with sex-specific effects.

## Key findings

- Fluoxetine restored hippocampal LTP in male mice after GCI but not in females.
- Fluoxetine increased BDNF expression in treated males but not in females.
- Ex vivo experiments confirmed LTP rescue in GCI-injured male slices with fluoxetine.

## Abstract

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.