Molecular psychiatryJul 31, 2026

MicroRNA-148a influences depression-like behavior in mice through brain development and dopamine signaling

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 3, 2026

Abstract

Conditional knockout of miR-148a in astrocytes improved cognitive performance and reduced anxiety and depression-like behaviors in mice.

Overexpression of miR-148a led to increased anxiety and depression-like behaviors in mouse models.
Astrocyte activation and neuronal damage were observed with miR-148a overexpression.
Deletion of miR-148a resulted in preserved neuronal integrity and improved synaptic structure.
Transcriptomic analysis identified Otx2 as a direct target of miR-148a, influencing dopaminergic signaling.
Metabolomic analysis revealed changes in neuroendocrine and neurotransmitter-related metabolic pathways.
Findings indicate that miR-148a plays a critical role in mood and cognitive regulation through interactions between astrocytes and neurons.

Simplified

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.

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PubMed

MicroRNA-148a influences depression-like behavior in mice through brain development and dopamine signaling

Abstract

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