Neuron-specific transcriptomic dysregulation in methotrexate-induced cognitive impairment revealed by SnRNA-seq
Jishi Ye1,2, Yu Ding1, Ruolan Wu3
1Department of Pain, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China.
International Journal of Surgery (London, England)
|September 24, 2025
Summary
Methotrexate (MTX) chemotherapy alters hippocampal neuron balance, causing cognitive impairment. This study reveals molecular mechanisms involving synaptic signaling disruptions, identifying potential therapeutic targets for chemotherapy-induced cognitive deficits.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Methotrexate (MTX) chemotherapy can cause neurotoxicity and cognitive impairments.
- The hippocampus is particularly vulnerable to MTX effects.
- Molecular mechanisms of MTX-induced cognitive dysfunction remain unclear.
Purpose of the Study:
- To investigate molecular mechanisms of MTX-induced cognitive impairment.
- To identify cellular and transcriptomic changes in the hippocampus following MTX treatment.
- To uncover potential therapeutic targets for MTX neurotoxicity.
Main Methods:
- Established a mouse model of MTX-induced cognitive impairment.
- Utilized single-nucleus RNA sequencing (snRNA-seq) to analyze hippocampal cell transcriptomes.
- Focused on neuron-specific gene expression changes after MTX exposure.
Main Results:
- MTX chemotherapy altered the balance of excitatory and inhibitory hippocampal neurons.
- Transcriptomic analysis revealed disrupted regulatory networks and trajectories in GABAergic neurons.
- MTX modulated Nrg1-Erbb4 and Nrxn3-Lrrtm4 pathways, affecting synaptic signaling and function.
Conclusions:
- MTX chemotherapy significantly impacts hippocampal cellular function and neural network balance.
- Specific molecular pathways and synaptic disruptions are implicated in MTX-induced cognitive deficits.
- Findings provide insights into potential therapeutic strategies for mitigating MTX neurotoxicity.
