Immaturity-Dependent Hippocampal Neurogenic Promotion and Fate Shift by Low-Dose Propofol in Neonatal Mice Revealed...

Background: Hippocampal neurogenesis in the dentate gyrus persists into adulthood and plays a crucial role in learning and memory. Early-life exposure to low-dose propofol has been reported to enhance neural development in rodent models, but detailed mechanisms remain unclear. To address this gap, we aimed to investigate how low-dose propofol alters neurogenic lineage differentiation, transcriptional programs, and underlying molecular mechanisms within the early postnatal hippocampal neurogenic niche. Results: We conducted an in-depth re-analysis of a published single-nucleus RNA-sequencing (snRNA-seq) dataset from hippocampal tissue of postnatal day 10 (PND10) mice, collected 3 days after low-dose propofol treatment. Uniform Manifold Approximation and Projection (UMAP)-based clustering revealed twelve major cell types, including a population of Ntng1⁺Fxyd7⁺Pcp1⁺ immature pyramidal neurons (imPYR), lacking the mature markers Meis2 and Spock1. Trajectory analysis revealed two neurogenic lineages (granule and pyramidal) and indicated that propofol biases progenitor fate commitment towards the granule lineage. CellChat analysis demonstrated that propofol enhances Neurexin (Nrxn) signaling to neural progenitor cells, suggesting increased synaptic adhesion and maturation. Differential expression analysis (|log₂FC| ≥ 0.26, adjusted p < 0.01) followed by pathway enrichment revealed that propofol upregulates neurogenic maturation pathways-including synaptogenesis, synaptic transmission, dendritic morphogenesis, and memory-related processes-specifically within neural intermediate progenitor cells (nIPC). Conclusions: Together, these findings delineate a coordinated transcriptional and intercellular mechanism by which low-dose propofol reprograms hippocampal neurogenesis during early postnatal development, highlighting progenitor-specific and synapse-oriented processes that may underlie its cognitive-enhancing effects.