From Depression-Associated Phospholipid Remodeling to Receptor-Active Lipid Signaling: The LPC-ATX-LPA Axis as a Testable Framework

Major depressive disorder (MDD) is increasingly understood as a disorder of integrated immune, endocrine, metabolic, neurovascular and synaptic regulation rather than a disease reducible to a single neurotransmitter deficit. Lipidomic studies have repeatedly identified glycerophospholipid abnormalities in MDD, but their mechanistic meaning remains unresolved because changes in bulk lipid abundance do not explain how a metabolic disturbance becomes a receptor-level neural signal. This review argues that the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidic acid (LPA)-LPA receptor (LPAR) axis offers a chemically and biologically coherent route for addressing that gap. LPC is not merely a readout of phospholipid remodeling; it is the direct ATX substrate from which receptor-active LPA can be generated. LPA receptors, in turn, regulate neural excitability, synaptic balance, hippocampal plasticity and stress-related behavior. Human studies report lower serum and cerebrospinal-fluid ATX in MDD, lower CSF LPA 22:6 in MDD and schizophrenia, and negative total-LPA findings that caution against biomarker oversimplification. Experimental studies show that ATX/LPA/LPAR perturbation alters hippocampal function, emotional behavior, stress resilience and synaptic physiology. These findings do not establish a completed depression pathway. They support a more specific hypothesis: depression-relevant ATX-LPA biology may be molecular-species resolved, compartment dependent, regionally organized and shaped by local production-inactivation balance. Reproductive endocrine transitions provide a biologically informative setting for testing this hypothesis because mood vulnerability, systemic lipid remodeling and steroid-sensitive regulation of pathway-adjacent nodes converge in the same clinical context. The decisive unresolved issue is spatial and biochemical: no depression-relevant study has yet demonstrated that defined brain-accessible LPC species, catalytically active ATX, locally generated LPA, local LPA inactivation capacity and receptor-specific circuit output coexist within a single mood-relevant CNS microenvironment. Future work should therefore move from fluid-level association toward pathway closure through targeted and spatial lipidomics, anatomical ATX activity mapping, LPA inactivation assays, BBB/interface analysis, LPAR perturbation and matched circuit or behavioral readouts.