Neuronal progranulin in the medial prefrontal cortex mediates stress-induced despair-like behaviors and impaired neuroplasticity.
Abstract
Background
Neuroplasticity in the medial prefrontal cortex (mPFC) is critically implicated in major depressive disorder (MDD). Progranulin (PGRN), a multifunctional protein that is abundant in the cortex, regulates neuronal development and synaptic maintenance, positioning it as a candidate therapeutic target for MDD. However, current findings indicate the effects of PGRN in depression are contingent upon both brain region and cell type. Whether neuronal PGRN in the mPFC contributes to the pathogenesis of depression remains unknown.
Methods
A chronic unpredictable mild stress (CUMS) mouse model was established, followed by depression-related behavioral tests. PGRN expression levels were determined by western blotting and immunofluorescence. Adeno-associated virus (AAV)-mediated neuronal Grn knockdown was performed in the mPFC in vivo to assess the functional contribution of PGRN. Neuronal morphology was evaluated by Golgi staining and Sholl analysis. Transcriptional changes were profiled by RNA sequencing to explore potential mechanisms, with bioinformatics analyses including differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network analysis.
Results
PGRN expression was increased in mPFC neurons after CUMS exposure. Neuronal Grn knockdown in the mPFC partially reversed CUMS-induced despair-like behaviors and impaired dendritic plasticity. Transcriptomic analysis further revealed that Grn knockdown restored CUMS-induced neuroplasticity-related transcriptional alterations, including genes involved in Ephrin signaling, planar cell polarity, and MYC-related transcriptional programs.
Conclusion
These findings suggest that neuronal PGRN in the mPFC contributes to the despair-like phenotype, likely through modulation of neuroplasticity. Targeting neuronal PGRN may represent a potential strategy for developing novel antidepressant interventions.