Delayed Fluoxetine Administration Restores Hippocampal Function in a Juvenile Global Cerebral Ischemia Mouse Model in...

Area of Science:

• Neuroscience
• Pediatric Neurology
• Pharmacology

Background:

• Global cerebral ischemia (GCI) in childhood causes significant cognitive deficits.
• Existing treatments for GCI survivors are limited, with no therapies to enhance recovery.
• Juvenile GCI leads to hippocampal synaptic dysfunction and reduced brain-derived neurotrophic factor (BDNF).

Purpose of the Study:

• To investigate if delayed fluoxetine (FLX) treatment could accelerate synaptic recovery after juvenile GCI.
• To determine the role of brain-derived neurotrophic factor (BDNF) and its signaling pathways in FLX-mediated recovery.
• To explore potential sex differences in response to FLX treatment following GCI.

Main Methods:

• Juvenile mice were subjected to cardiac arrest and cardiopulmonary resuscitation to induce GCI.
• Fluoxetine (FLX) or vehicle was administered from postinjury days 10-13.
• Electrophysiological recordings (long-term potentiation - LTP) and hippocampal BDNF expression were assessed.

Main Results:

• FLX treatment restored hippocampal LTP in male GCI survivors but not in females.
• Hippocampal BDNF expression increased in FLX-treated males, but not females.
• Ex vivo experiments confirmed FLX's ability to rescue LTP in male GCI-injured brain slices.

Conclusions:

• Delayed FLX treatment promotes synaptic recovery in male juvenile GCI survivors, potentially via BDNF-TrkB signaling.
• Female GCI survivors may utilize hormone-dependent mechanisms for recovery, independent of FLX's effects on BDNF.
• These findings highlight a therapeutic window for enhancing neuroplasticity post-GCI and emphasize the importance of sex and developmental stage in treatment response.