Evaluation of a Structural Restoration Strategy to Enhance Antidepressant Response in Major Depression: Effects of GM1 Oligosaccharide (osGM1) Combined with Desipramine in a Murine Model

Major depression is a leading global health concern and cause of disability. A considerable proportion of patients exhibit limited responsiveness to conventional antidepressants, suggesting incomplete recovery of synaptic plasticity and structural connectivity in fronto-hippocampal circuits. We hypothesize that combining the ganglioside GM1 oligosaccharide (osGM1) with desipramine (DMI), a tricyclic antidepressant, will enhance therapeutic efficacy through BDNF-TrkB-dependent structural restoration. In a murine model of chronic distress induced by social isolation and repeated restraint stress, osGM1+DMI dosing will be optimized to evaluate behavioral and endocrine endpoints. Parallel analyses in Thy1-GFP mice will quantify dendritic spine density and morphology, neuronal arbor complexity, hippocampal neurogenesis, TrkB-ERK/AKT-CREB signaling, and synaptic protein expression across fronto-hippocampal regions. We will test TrkB involvement using the antagonist ANA-12. We will then evaluate the optimized treatment in BDNF Val66Met knock-in mice, a model of reduced BDNF secretion and antidepressant responsiveness. Finally, maternal treatment during gestational distress will be evaluated for its capacity to prevent behavioral, endocrine, and epigenetic alterations in adult offspring, providing insight into the intergenerational mechanisms of antidepressant efficacy.