Prdm15 Deficiency Results in Impaired Hippocampal Neurogenesis and Autism-Like Behaviors

Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder, with epidemiological studies consistently reporting a rising prevalence worldwide. Our previous human genetic sequencing analysis identified PRDM15 (PRDI-BF1 (Positive regulatory domain I-binding factor 1) and RIZ1 (Retinoblastoma protein-interacting zinc finger 1) homologous domain-containing protein 15), a transcriptional regulator and a member of the PRDM family, as a novel candidate risk gene for ASD. However, its precise role in brain development and subsequent behavioral outcomes remains unclear. Here, we demonstrate that Prdm15 deficiency in mice recapitulates core autism-like behaviors, including increased repetitive grooming, deficits in social interaction, and impaired social recognition memory. Structural MRI (Magnetic resonance imaging) and histological analyses revealed abnormal hippocampal architecture, characterized by reduced neuronal density in the CA1 (Cornu Ammonis 1) subregion. Through single-cell RNA sequencing of the developing hippocampus in mice, we found that Prdm15 deficiency impaired neurogenic lineage differentiation, leading to an accumulation of neural stem cells and a concomitant reduction in mature neurons, which were associated with transcriptional alterations in these cells. Crucially, conditional ablation of Prdm15 specifically in neural stem/progenitor cells achieved by crossing Prdm15-floxed mice (Prdm15^fl/fl) with the Nestin-Cre strain, was sufficient to partially recapitulate the cellular and behavioral phenotypes observed in constitutive Prdm15-deficient mice. Collectively, our findings identify PRDM15 as a critical regulator of hippocampal neurogenesis and provide evidence that its dysfunction contributes to the pathogenesis of ASD-like behaviors in mice.