Hyper-maturity and accelerated aging in the hippocampus of mouse models of neuropsychiatric disorders with anxiety-like behavior

Abstract

Proper maturation of neuronal and glial cells in the hippocampus is essential for emotional regulation and cognitive function. While pseudo-immaturity, defined as arrested or reversed development, has been extensively implicated in various neuropsychiatric conditions, the opposite phenomenon, hyper-maturity, remains underexplored. Here, we present transcriptomic evidence of hippocampal hyper-maturity across 17 datasets from 16 mouse models with genetic, pharmacological, or other experimental manipulations, identified through a comprehensive screening of over 260,000 omics datasets. These models were characterized by a pronounced overrepresentation of gene expression changes typically observed during postnatal development and included serotonin transporter knockout mice, glucocorticoid receptor overexpressing mice, and corticosterone-treated mice, models of depression and anxiety, Df(16)A+/− mice, a 22q11.2 deletion schizophrenia model, β-glucuronidase-deficient lysosomal storage disorder model mice, and senescence-prone SAMP8 mice. Meta-analysis of enriched pathways highlighted associations of synapse-related genes with the hyper-maturity signature. Behavioral annotations from public datasets further suggest that hippocampal hyper-maturity models predominantly exhibit increased anxiety-like behaviors, whereas immaturity models tend to display the opposite pattern. Notably, hippocampal hyper-maturity encompassed two transcriptional dimensions: enhanced postnatal development and accelerated aging. For example, SAMP8 mice aligned more with developmental enhancement, whereas corticosterone-treated and lysosomal storage disorder models reflected aging acceleration. Combined analysis with available single-cell RNA-sequencing data further delineated that microglia and granule cells may contribute to aging-associated transcriptional shifts. These findings suggest that hippocampal hyper-maturity and accelerated aging represent convergent molecular phenotypes associated with anxiety-like behavior. Bidirectional alterations in hippocampal maturity may serve as a transdiagnostic endophenotype and offer novel therapeutic or anti-aging targets for neuropsychiatric disorders.