Neuronal activity-regulated histone demethylase KDM7A controls hippocampal gene expression and behavior.

The role of lysine demethylase 7A (KDM7A) in the mammalian brain remains largely unexplored. Here, we demonstrate that KDM7A occupies thousands of genomic loci in hippocampal chromatin and that both its expression and chromatin binding are dynamically regulated by neuronal activity in culture and in vivo. To define its functional relevance, we generated mouse models with either complete loss of KDM7A or disrupted enzymatic activity and assessed neurological phenotypes. Integrating cellular and molecular analyses with transcriptomic and chromatin-occupancy profiling and behavioral assessments, we show that KDM7A is required for the proper transcriptional regulation of genes implicated in neuronal physiology and synaptic plasticity. In line with these transcriptional alterations, KDM7A-deficient mice display hyperlocomotion, reduced anxiety-like behavior, decreased sensitivity to pro-epileptic agents, and task-dependent changes in cognitive performance. Together, our findings identify KDM7A as a key epigenetic regulator of neuronal gene expression and behavior in the mammalian brain.