The synaptic triad in depression: how stress-related pathways converge on BDNF, NMDA receptor, and MMP-9.

Chronic stress is a major precipitating factor in depression, engaging interconnected central and peripheral pathways. In this review, we propose an integrative model that organizes the neurobiological consequences of stress around five major mechanistic domains: neurotrophic dysfunction, disturbances in inhibition-excitation (E/I) balance, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, neuroinflammatory activation, and monoaminergic alterations. Although each hypothesis highlights distinct aspects of stress-related pathology, we argue that they ultimately converge on shared molecular mediators, including matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate (NMDA) receptor-dependent signalling, that govern synaptic plasticity.In this model, synaptic plasticity emerges as the final common mechanism through which chronic stress produces enduring alterations in brain structure and function. Context-dependent modulation of MMP-9 activity, dysregulated BDNF processing, NMDA-dependent control of synaptic strength, and monoaminergic influences on neurotrophic and glial function collectively impair synaptic plasticity. As a result, stress-driven pathways lead to altered dendritic spine architecture, reduced neurogenesis, and maladaptive network-level changes underlying depressive behavior. By positioning synaptic plasticity as the convergent endpoint of diverse stress-responsive mechanisms, the model highlights common therapeutic targets, including MMP-9 modulation, BDNF-enhancing strategies, HPA-axis regulators, anti-inflammatory approaches, and NMDA receptor-based interventions, offering new directions for mechanism-based and personalized treatments in depression.