¹The First Affiliated Hospital of Chongqing Medical University, Psychiatric Center, Chongqing, China, ²University-Town Hospital of Chongqing Medical University, Psychiatry, Chongqing, China

Background: Major depressive disorder (MDD) is a leading cause of disability worldwide. A significant number of patients, particularly adolescents, do not respond well to existing treatments. Electroconvulsive therapy (ECT) is one of the most effective neurostimulation therapies for severe MDD. However, its underlying molecular mechanisms remain unclear.

Aims & Objectives: This study aims to identify specific, druggable pathways that mediate the remarkable therapeutic effects of ECT. The ultimate goal is to provide a foundation for developing new treatment strategies for adolescent MDD.

Method: We used a translational research pipeline. First, we performed high-throughput miRNA sequencing on blood samples from adolescent MDD patients before and after ECT. We then translated these clinical findings into a chronic unpredictable mild stress (CUMS) mouse model. In these mice, we applied electroconvulsive stimulation (ECS) and used behavioral tests, PET imaging, and immunofluorescence for further validation. Most importantly, we performed endogenous gain and loss of function experiments targeting the identified miRNA and its target gene in the mouse dentate gyrus (DG). This was done to establish a causal relationship with the antidepressant response.

Results: Both MDD patients (plasma) and CUMS mice (plasma and hippocampus) showed elevated miR-221-3p levels, which decreased after ECT/ECS alongside symptom improvement. DG miR-221-3p overexpression blocked ECS benefits by targeting CDH2, impairing neurogenesis and worsening apoptosis and synaptic damage. Conversely, miR-221-3p knockdown mimicked ECS effects by promoting neurogenesis, rescuing apoptosis and synaptic damage and improving depressive-like behaviors.

Discussion & Conclusions: Our study defines the miR-221-3p/CDH2 pathway as a critical and previously unrecognized mediator of both depression pathophysiology and ECT's therapeutic action. These findings not only provide a mechanistic explanation for ECT's efficacy but, more importantly, position the miR-221-3p/CDH2 axis as a promising and druggable target for the development of novel, circuit-specific pharmacotherapies for treatment-resistant depression.