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 the neuronal genome and thereby proper brain functions. Emerging evidence links DNA repair to epigenetic gene regulation; however, its contribution to different transcriptional programs required for neuronal functions remains elusive. In this study, we identified a role of the DNA repair enzyme NEIL3 in modulating the maturation and function of hippocampal CA1 neurons by shaping the CA1 transcriptome during postnatal development and in association with spatial behavior. We observed a delayed maturation in Neil3(-/-) CA1 and identified differentially regulated genes required for hippocampal development. We revealed impaired spatial stability in Neil3(-/-) CA1 place cells and found spatial experience-induced gene expression essential for synaptic plasticity. This is the first study that links molecular underpinnings of DNA repair to the neural basis of spatial cognition beyond animals' behavioral phenotypes, thus shedding light on the molecular determinants enabling a stable neural representation of space.