The Role of Calcium-Independent Phospholipase A2 in the Molecular Mechanisms of Schizophrenia

Schizophrenia, depression, and bipolar disorder may represent neurodegenerative conditions involving both degeneration and aberrant regeneration of monoaminergic axons. Negative and cognitive symptoms could arise from monoaminergic axon degeneration, whereas positive symptoms and manic states might result from excessive axonal regeneration and sprouting. The molecular mechanisms driving these opposing processes remain largely unclear. This review considers the possible role of calcium-independent phospholipase A₂ (iPLA2) in regulating monoamine axon degeneration and hyper-regeneration in schizophrenia. Emerging evidence suggests that pro-inflammatory signaling mediated by cytosolic PLA₂ (cPLA2) may promote monoamine axon degeneration, while anti-inflammatory iPLA2 activity could facilitate regeneration and sprouting. Overactivation of iPLA2 might lead to aberrant axonal sprouting, potentially contributing to positive symptoms through hyperdopaminergic states in the medial prefrontal cortex (mPFC). Conversely, axon degeneration in the same region may underlie negative and cognitive symptoms. The review also discusses a potential interplay between dopamine and N-methyl-D-aspartate (NMDA) receptor signaling in distinct neuronal populations of the mPFC and suggests that targeting iPLA2 and its pathways could represent a promising therapeutic strategy. Viewing schizophrenia and related disorders through the lens of monoamine axon pathology may eventually improve diagnostic precision and inform the development of treatments aimed at restoring the balance between degeneration and regeneration.