CXCL12/CXCR4 axis as a modulator of neurotransmission in depression: A neuroimmune perspective

Major Depressive Disorder (MDD) is characterized by heterogeneous pathogenesis that extends beyond traditional monoamine deficits. A paradigm shift is recognizing neuroinflammation as a central, critical driver of both illness onset and resistance to treatment. The CXCL12/CXCR4 system is traditionally associated with immune cell trafficking, but increasing evidence reveals its powerful regulatory role in neuropsychiatric disorders. We performed a comprehensive synthesis demonstrating that CXCL12/CXCR4 axis acts as a direct molecular modulator of neurotransmission, neuroplasticity, and glial cell signaling. Specifically, this axis can modulate a multiple molecular pathways linked with the glutaminergic, GABAergic, and serotonergic systems, and mediating neuroplasticity and glial cell function. Functionally, CXCL12/CXCR4 axis has twofold character - it can strengthen neurotoxic processes through overactivation of NMDAR and excessive Ca2 + influx. On the other hand, it can also play protective role by preventing excitotoxicity, supporting neurogenesis, enhancing GABA synthesis, and dendritic spines stabilization. This review focuses on identifying potential mechanisms across in vitro, animal, and human studies to establish the CXCL12/CXCR4 axis as a powerful biomarker and, critically, an unexploited therapeutic target.