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Microglia-Mediated Synaptic Dysfunction Contributes to Chemotherapy-Related Cognitive Impairment
Jingxiong Wang1, Hua Zhang1, Marc Augenreich2
1Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, USA.
Abstract:
Chemotherapy-related cognitive impairment (CRCI) significantly impacts cancer survivors. Due to unclear mechanisms, effective treatments for cognitive deficits are lacking. Here, we examined if microglia-mediated deficits in synaptic plasticity drive CRCI. Adult male mice were treated with the chemotherapeutic drugs 5-fluorouracil and leucovorin (5-Fu/LV, intraperitoneal injection, I.P.) on Days 1, 8, and 15 at a dosage of 50 mg/kg for 5-Fu and 90 mg/kg for LV for 3 weeks. Cognitive function was assessed using a novel object recognition (NOR) test 4 weeks after completion of 5-Fu/LV treatment. Compared with vehicle treatment, 5-Fu/LV treatment reduced the preference for exploring novel objects in the NOR test. Treatment with 5-Fu/LV increased the numbers of Iba1-positive microglial and CD68-positive/Iba1-positive microglia with shortened process lengths and diminished endpoints but decreased the number of phagocytotic (≤ 1 FITC-labeled beads) Iba1-positive microglia. Furthermore, 5-Fu/LV treatment reduced the long-term potentiation (LTP) recorded in the hippocampal CA1 region in response to a theta burst stimulation of the CA3-CA1 pathway and decreased the evoked N-methyl-D-aspartic acid receptor (NMDAR)-excitatory postsynaptic currents (NMDAR-EPSCs) in CA1 neurons. Cotreatment with the microglial inhibitor minocycline (33 mg/kg, daily for 3 weeks) restored cognitive deficits and microglial ramification, decreased the number of CD68-positive microglia, and reversed the reductions in LTP and the amplitude of NMDAR-EPSCs in 5-Fu/LV-treated mice. Our data suggest that microglial dysfunction and related synaptic dysfunction contribute to 5-Fu/LV-induced cognitive impairment.
Insights
Chemotherapy impairs cognition by affecting microglia and synaptic plasticity. Minocycline treatment reversed these effects, suggesting microglial dysfunction drives chemotherapy-related cognitive impairment (CRCI).
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.
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