DNA repair enzyme NEIL3 enables a stable neural representation of space by shaping transcription in hippocampal neurons

DNA repair enzymes are essential for the maintenance of neuronal genome and thereby proper brain functions. NEIL3 is a member of the NEIL family DNA glycosylases initiating oxidative DNA base excision repair. Recent studies show that NEIL3-deficiency leads to impaired spatial performance in mice, decreased adult neurogenesis and altered synaptic composition in the hippocampus. However, it remains elusive how NEIL3 contributes to spatial information coding in hippocampal neurons. Here, we revealed impaired spatial stability in Neil3-/- CA1 place cells, demonstrating a functional interference of NEIL3 with spatial representations. We identified NEIL3-dependent transcriptional changes in response to spatial exploration and defined its regulatory role specifically for NMDA receptor subunits and immediate early genes. Our work demonstrates a non-canonical role of NEIL3 in modulating the functional plasticity of place cells by shaping the neuronal transcriptome, thus sheds light on the molecular determinants enabling a stable neural representation of space.