The histone lysine demethylase KDM7A contributes to reward memory via Fscn1-induced synaptic plasticity in the medial prefrontal cortex

Lysine demethylase 7A (KDM7A) catalyzes the removal of dimethylation from histone H3 lysine 9 and lysine 27, both of which are associated with transcription repression. Previous study indicated that Kdm7a mRNA in the medial prefrontal cortex (mPFC) increased after drug exposure, yet its role in drug-related behaviors is largely unknown. In a morphine-conditioned place preference (CPP) paradigm, our findings revealed a specific increase of Kdm7a expression in the mPFC seven days after drug withdrawal. Subsequently, our results demonstrated that knockdown of Kdm7a in the mPFC did not affect the acquisition of morphine-induced CPP, but it attenuated memory consolidation. To further explore Kdm7a-mediated transcriptomic changes, we employed Nanopore direct RNA sequencing. Transcriptome profiling unveiled several gene expression alterations impacted by KDM7A, which were enriched in relevant neural function categories. Notably, we identified and validated fascin actin-bundling protein 1 (Fscn1) as a downstream molecular target. Knockdown of Fscn1 had a similar impact on CPP to Kdm7a, along with a corresponding decrease in dendritic spine density in the mPFC. Additionally, ChIP analysis demonstrated that silencing Kdm7a in N2a cells resulted in decreased enrichment of H3K9me2 and H3K27me2 at the Fscn1 promoter region, suggesting that Kdm7a may act as a crucial regulator of transcriptional responses to morphine-related reward memory via Fscn1. Overall design: To investigate the regulatory role of KDM7A in the mPFC during the process of morphine addiction, we established a morphine addiction CPP model by knocking down KDM7A using shRNA in mice in the experimental group, with a control group for comparison. The two groups were further divided into saline and morphine subgroups. Subsequently, gene expression profiling was conducted on the RNA sequencing data obtained from mPFC tissue on the seventh day of morphine withdrawal.