Neuron-specific transcriptomic dysregulation in methotrexate-induced cognitive impairment revealed by SnRNA-seq

Methotrexate (MTX) is a widely used chemotherapy drug, but its neurotoxicity can lead to cognitive impairments, particularly through effects on hippocampal function. Nevertheless, the underlying molecular mechanisms are not fully understood. Deciphering MTX-induced cognitive impairment-linked molecular mechanisms in cells of the hippocampus could uncover novel therapeutic targets.

In this study, we established a mouse model of cognitive impairment induced by the chemotherapy drug MTX. We applied single-nucleus RNA sequencing (snRNA-seq) to analyze the transcriptomic alterations in hippocampal cells of mice following MTX treatment, with a focus on neuron-specific gene expression changes.

MTX chemotherapy led to a decrease in excitatory neurons but an increase in inhibitory neurons, altering the excitatory-inhibitory balance of neural networks and thus mediate cognitive dysfunction. Furthermore, MTX significantly disrupted the transcriptional regulatory network and potential trajectory of GABAergic neurons. It enhanced the Nrg1-Erbb4 pathway while attenuating the Nrxn3-Lrrtm4 pathway, destabilizing trans-synaptic signaling and causing abnormalities in excitatory and inhibitory synaptic functions. These disruptions may ultimately lead to neural network imbalance and cognitive dysfunction.

This study highlights the specific effects of MTX chemotherapy on hippocampal cellular function and provides valuable insights into the molecular mechanisms underlying cognitive deficits and potential therapeutic targets.