Schizophrenia pathogenesis: the role of prenatal influences

Schizophrenia is a multifactorial psychiatric disorder whose manifestation is driven by a complex interplay between genetic susceptibility and environmental adversity. Adverse prenatal exposures, including maternal infections, psychosocial stress, and fetal hypoxia, play a critical role in shaping neurobiological vulnerability during sensitive periods of neuroontogenesis. Maternal immune activation and chronic stress elicit a systemic inflammatory cascade characterized by the overproduction of pro-inflammatory cytokines (IL-6, IL-17, IL-1β, and TNF-α). These inflammatory mediators compromise the permeability of the fetal blood-brain barrier, trigger persistent microglial activation, and upregulate the kynurenine pathway of tryptophan metabolism, subsequently leading to aberrant synaptic pruning and NMDA receptor dysfunction. Concurrently, prenatal stress driven by excessive maternal glucocorticoids disrupts the regulatory loops of the hypothalamic-pituitary-adrenal axis, downregulates central glucocorticoid receptor expression, and impairs BDNF–TrkB-mediated neurotrophic support. Intrauterine hypoxia activates HIF-1α and the Notch signaling cascade, shifting neural stem cell differentiation toward astrogliogenesis while depleting cellular antioxidant defenses. A universal epigenetic predictor underlying these abnormalities is their consolidation through altered DNA methylation profiles and histone modifications, particularly within the regulatory regions of the GAD1 , BDNF , and RELN genes. These persistent changes culminate in postnatal structural abnormalities of the prefrontal cortex and hippocampus, as well as chronic GABAergic and glutamatergic neurotransmission deficits. In conclusion, heterogeneous prenatal triggers converge on distinct immune, endocrine, and epigenetic pathways to establish the morphofunctional substrate of vulnerability to schizophrenia, ultimately disrupting neural network maturation and the excitation-inhibition balance in the central nervous system.