Authors
Yifan Tang, Huicong Feng, Yue Li, Lupeng Zhang, Chiwen Qu, Tianai Zhu, Doudou Zhang, Yi Wen, Xiaomin Zeng, Yong Zhang, Xiaoning Peng
Published in
Molecular psychiatry. Jul 31, 2026. Epub Jul 31, 2026.
Abstract
MicroRNA-148a (miR-148a) has been implicated in various neurological disorders, yet its specific function within the central nervous system remains elusive. In this study, conditional astrocyte-specific miR-148a knockout (cKO) and overexpression (KI) mouse models were established using CRISPR-Cas9 and Cre-loxP technology to elucidate its role in emotional and cognitive regulation. Behavioral analyses demonstrated that miR-148a overexpression induced marked anxiety- and depression-like behaviors, accompanied by astrocyte activation, neuronal ultrastructural damage, and disrupted synaptic morphology. Conversely, miR-148a deletion preserved neuronal integrity, improved synaptic architecture, and produced anxiolytic and antidepressant phenotypes with enhanced cognitive performance. Transcriptomic profiling identified the transcription factor Otx2 as a direct target of miR-148a, mediating downstream modulation of dopaminergic signaling and neurodevelopmental genes. Integrative metabolomic analysis further revealed coordinated alterations in neuroendocrine and neurotransmitter-associated metabolic pathways. Collectively, these findings demonstrate that miR-148a critically modulates astrocyte-neuron interactions and dopaminergic homeostasis through the OTX2 axis, contributing to mood and cognitive disturbances. This work provides mechanistic insight into miR-148a-mediated neuroregulation and highlights its potential as a therapeutic target for affective and cognitive disorders.
PMID:
42538392
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.
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