Zinc transporter-3 as a novel target for fast and long-lasting antidepressant actions

Major Depressive Disorder (MDD) is a leading cause of disability worldwide, with up to 30% of patients developing treatment-resistant depression (TRD). There is an urgent need for novel therapeutic targets that drive rapid and sustained antidepressant effects.Zinc transporter-3 (ZnT3) is a novel and unexplored target. We recently showed that psilocybin enhances proliferation and survival of human hippocampal progenitor cells and promotes neurogenesis and neurite outgrowth. Single-cell RNAseq indicates stage-specific ZnT3 expression, suggesting a role in neurogenesis. In mice, we showed that ZnT3 expression and the activation of adult-born neurons are required for psilocybin’s rapid and lasting antidepressant effects. This project will validate ZnT3 as a novel therapeutic target to elicit rapid and long-lasting effects without hallucinogenic effects, by examining its role in neuroplasticity using preclinical models and patient-derived samples. First, we will assess ZnT3 expression in adult-born neurons following chronic stress and antidepressant treatment, in mice and brain-derived exosomes from MDD and TRD patients. Second, we will determine whether modulating ZnT3 or increasing intracellular Zinc elicits antidepressant-like effects.Targeting ZnT3 will offer a new therapeutic approach for MDD, with the potential to provide rapid and long-lasting benefit to patients resistant to existing treatments.