Dissecting gene expression networks in the developing hippocampus through the lens of NEIL3 depletion.

Gene regulation in the hippocampus is fundamental for its development, synaptic plasticity, memory formation, and adaptability. Comparisons of gene expression among different developmental stages, distinct cell types, and specific experimental conditions have identified differentially expressed genes contributing to the organization and functionality of hippocampal circuits. The NEIL3 DNA glycosylase, one of the DNA repair enzymes, plays an important role in hippocampal maturation and neuron functionality by shaping transcription. While differential gene expression (DGE) analysis has identified key genes involved, broader gene expression patterns crucial for high-order hippocampal functions remain uncharted. By utilizing the weighted gene co-expression network analysis (WGCNA), we mapped gene expression networks in immature (p8-neonatal) and mature (3 m-adult) hippocampal circuits in wild-type and NEIL3-deficient mice. Our study unveiled intricate gene network structures underlying hippocampal maturation, delineated modules of co-expressed genes, and pinpointed highly interconnected hub genes specific to the maturity of hippocampal subregions. We investigated variations within distinct gene network modules following NEIL3 depletion, uncovering NEIL3-targeted hub genes that influence module connectivity and specificity. By integrating WGCNA with DGE, we delve deeper into the NEIL3-dependent molecular intricacies of hippocampal maturation. This study provides a comprehensive systems-level analysis for assessing the potential correlation between gene connectivity and functional connectivity within the hippocampal network, thus shaping hippocampal function throughout development.

NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice.

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1-/-Neil2-/- mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1-/-Neil2-/- mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.