Metformin alleviates type 2 diabetes-related depressive-like behaviors via AKAP150 signaling in NAc D1 medium spiny...

Type 2 diabetes mellitus (T2DM) exhibits high comorbidity with depression, and progressive synaptic maladaptation of D1- and D2-expressing medium spine neurons (D1/D2-MSNs) in the nucleus accumbens (NAc) is critical involved in this pathological process. The first-line hypoglycemic drug metformin has been suggested to alleviates depressive symptoms. A-kinase anchoring protein 150 (AKAP150) modulates postsynaptic AMPA receptor (AMPAR) phosphorylation and synaptic function. However, the cell-type-specific role of AKAP150 in T2DM-related depression and its relevance to metformin's antidepressant mechanism remain unclear. Here, we established T2DM mouse models with depressive-like behaviors using D1-Cre and D2-Cre transgenic mice, combined with RNA sequencing, immunofluorescence, and electrophysiology and viral genetic manipulation to dissect NAc AKAP150 signaling. We detected specific downregulation of AKAP150 exclusively in D1-MSNs (rather than D2-MSNs) of T2DM mice and its expression level negatively correlated with the severity depressive-like phenotypes. Cell-specific overexpression of wild-type AKAP150 in D1-MSNs restored AMPAR-mediated synaptic transmission, corrected aberrant dendritic spine remodeling, and rescued T2DM-related depressive-like behaviors. In contrast, overexpression of a PKA-binding-deficient AKAP150 mutant failed to reverse these effects. Notably, metformin treatment selectively restored AKAP150 expression in D1-MSNs, rescued synaptic deficits and abnormal spine morphology, and alleviated T2DM-related depressive-like behaviors. Specifically, genetic and pharmacological disruption of AKAP150-PKA signaling fully abolished metformin's antidepressant. In summary, the AKAP150-PKA-AMPAR signaling cascade in NAc D1-MSNs serves as an essential molecular mediator of T2DM-related depressive-like behaviors in mice, and is required for the therapeutic effects of metformin. This study offers a cell-type-specific mechanism and provides a promising targeted strategy for treating diabetes-depression comorbidity.