Microglia-Mediated Synaptic Dysfunction Contributes to Chemotherapy-Related Cognitive Impairment

Area of Science:

• Neuroscience
• Oncology
• Pharmacology

Background:

• Chemotherapy-related cognitive impairment (CRCI) is a significant challenge for cancer survivors.
• The underlying mechanisms of CRCI remain unclear, limiting effective treatment development.
• Microglia and synaptic plasticity are potential key players in CRCI pathogenesis.

Purpose of the Study:

• To investigate if microglia-mediated deficits in synaptic plasticity contribute to CRCI.
• To determine the effects of 5-fluorouracil and leucovorin (5-Fu/LV) on cognitive function, microglial activity, and synaptic plasticity in mice.
• To assess the therapeutic potential of minocycline in mitigating 5-Fu/LV-induced cognitive deficits.

Main Methods:

• Adult male mice received 5-Fu/LV chemotherapy or vehicle treatment.
• Cognitive function was evaluated using the novel object recognition (NOR) test.
• Microglial morphology and activity were assessed via Iba1 and CD68 staining.
• Hippocampal long-term potentiation (LTP) and N-methyl-D-aspartic acid receptor-excitatory postsynaptic currents (NMDAR-EPSCs) were measured.
• Mice were co-treated with the microglial inhibitor minocycline.

Main Results:

• 5-Fu/LV treatment induced cognitive deficits in the NOR test.
• Chemotherapy altered microglial morphology, increasing CD68-positive microglia and reducing phagocytosis.
• 5-Fu/LV reduced hippocampal LTP and NMDAR-EPSCs.
• Minocycline treatment restored cognitive function, normalized microglial changes, and reversed synaptic plasticity deficits.

Conclusions:

• Microglial dysfunction, characterized by altered morphology and reduced phagocytosis, is implicated in chemotherapy-induced cognitive impairment.
• Synaptic plasticity deficits, specifically reduced LTP and NMDAR-EPSCs, contribute to CRCI.
• Targeting microglial activity with agents like minocycline may offer a therapeutic strategy for CRCI.