MicroRNA-148a regulates depressive-like behaviors in mice via the Otx2/Dopaminergic signaling axis

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.