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Targeting miR-335-3p restores neural stem cell proliferation and ameliorates cognitive impairment in gestational dexamethasone-exposed offspring

ABSTRACT: Prenatal overexposure to glucocorticoids (GC) can lead to cognitive impairment in offspring, yet the underlying mechanisms remain elusive, and effective clinical interventions are still lacking. In this study, we analyzed the miRNA expression profile in hippocampal neural stem cells (NSCs) from gestational synthetic GC analog dexamethasone (DEX) exposure (GDE) offspring mice, and found that miR-335-3p expression was significantly downregulated. Functional experiments demonstrated that miR-335-3p specifically reverses the inhibitory effect of DEX on NSC proliferation without affecting their differentiation capacity. Mechanistic studies revealed that DEX activates the glucocorticoid receptor (GR) to directly suppress miR-335-3p transcription, which in turn relieves its targeted inhibition of PTEN, ultimately impairing NSC proliferation and cognitive function. This DEX/miR-335-3p/PTEN regulatory axis is highly conserved in human embryonic stem cells (hESCs)-derived 2D NSCs and 3D cerebral organoids. Importantly, intrahippocampal delivery of miR-335-3p agomir effectively restored NSC proliferation and ameliorated learning and memory deficits in GDE offspring mice. These findings identify a previously unrecognized miRNA-mediated epigenetic axis underlying prenatal GC exposure-induced cognitive impairment in offspring. Our study provides mechanistic insights into the developmental origins of glucocorticoid-induced neurological disorders and highlights miR-335-3p as a potential therapeutic target for preventing fetal-origin cognitive deficits.

ORGANISM(S): Mus musculus

PROVIDER: GSE330808 | GEO | 2026/05/18

REPOSITORIES: GEO

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