BDNF and GSK-3β Dysregulation Drives Neuroplasticity Dysfunction in Depression

Major depressive disorder (MDD) is a complex psychiatric condition marked by persistent low mood, emotional dysregulation, and significant cognitive impairment. Current antidepressant therapies often have delayed onset of action and limited efficacy for many patients, highlighting a critical need for novel therapeutic targets. Emerging evidence points to impaired neuroplasticity as a core pathological feature. Specifically, dysregulation of brain-derived neurotrophic factor (BDNF) signaling and aberrant glycogen synthase kinase-3 beta (GSK-3β) activity are implicated in the synaptic and cellular dysfunction observed in depression.

This comprehensive review systematically synthesized current preclinical and clinical findings to elucidate the independent and interactive roles of BDNF and GSK-3β in the pathophysiology of depression. The authors analyzed a broad spectrum of research covering molecular mechanisms that link these two factors to synaptic deterioration, oxidative imbalance, neuroinflammatory responses, and hippocampal dysfunction. The review also explored emerging therapeutic strategies that specifically target the BDNF-GSK-3β signaling axis, evaluating compounds such as metformin, famotidine, tideglusib, lithium, and ketamine for their potential to restore neural plasticity.

The review highlights that attenuated BDNF levels and dysregulated GSK-3β activity are critical contributors to the impaired neuroplasticity characteristic of depression. Reduced BDNF signaling directly compromises neuronal survival, differentiation, and synaptic plasticity, while hyperactive GSK-3β exacerbates these effects by promoting neuronal apoptosis and inhibiting neurogenesis. The interplay between these two factors is crucial: GSK-3β can negatively regulate BDNF expression and function, creating a vicious cycle that impairs synaptic integrity and overall brain function. This dysregulated crosstalk leads to hallmark features of depressive pathology, including synaptic deterioration, increased oxidative stress, and heightened neuroinflammatory responses. > The altered interaction between BDNF and GSK-3β signaling pathways is a central mechanism underlying the observed neuroplasticity dysfunction in depression, suggesting it as a promising and actionable therapeutic target. The review also identified several compounds, including ketamine, that modulate this axis, offering new avenues for antidepressant development.