The mammalian positioning system contains a variety of functionally specialized cells in the medial entorhinal cortex (MEC) and the hippocampus. In order for cells in these systems to dynamically update representations in a way that reflects ongoing movement in the environment, they must be able to read out the current speed of the animal. Speed is encoded by speed-responsive cells in both MEC and hippocampus, but the relationship between the two populations has not been determined. We show here that many entorhinal speed cells are fast-spiking putative GABAergic neurons. Using retrograde viral labeling from the hippocampus, we find that a subset of these fast-spiking MEC speed cells project directly to hippocampal areas. This projection contains parvalbumin (PV) but not somatostatin (SOM)-immunopositive cells. The data point to PV-expressing GABAergic projection neurons in MEC as a source for widespread speed modulation and temporal synchronization in entorhinal–hippocampal circuits for place representation.

The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.

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.

Background: Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency. Results: We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial–temporal regulation of histone arginine methylation in specific brain regions. Conclusions: This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.

Neonatal hypoxic-ischemic (H-I) brain injury, a leading cause of neurodevelopmental disabilities, severely affects the metabolically active and neurogenic hippocampus. To investigate its acute effects and identify drug targets for early therapeutic windows, we applied single-nucleus RNA sequencing on postnatal day 8 (P8) mouse hippocampi under sham, hypoxic, and hypoxic-ischemic conditions. We constructed a comprehensive hippocampal cell atlas and developed a machine-learning classifier for precise cell type identification. Our analysis reveals early vulnerabilities in mature neurons and notable resilience in immature DG, GABAergic, and Cajal-Retzius cells following H-I. Gene regulatory network analysis identified key transcription factors associated with neuronal vulnerability, along with upregulated ribosome biogenesis and dysregulated calcium homeostasis pathways. We observed rapid activation of astrocytes and microglia, with Runx1 identified as a potential key transcription factor associated with early microglia immune responses. Endothelial cells displayed complex transcriptional changes and predicted intercellular signaling patterns that may influence vascular repair and recovery. Our study advances the understanding of immediate cellular and transcriptional responses to neonatal H-I injury, providing new insights into hippocampal cell heterogeneity and pathophysiology. The integrated hippocampal atlas, post-H-I atlas, and machine learning classifier are available at https://hippo-seq.org.

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.