Abstract Schizophrenia is a complex chronic mental disorder, revealed in adolescence or early adulthood, and is manifested by cognitive, emotional, and behavioral abnormalities. Owing to its complex nature and poor prognosis methods, multiple hypothesis have been proposed on the origin of schizophrenia. The neurodevelopmental hypothesis posits that schizophrenia arises from the intricate interplay of genetic, environmental, and neurobiological factors. These in turn lead to a considerable disruption in brain development during critical periods, particularly in fetal growth, early childhood, and adolescence. Disruptions in neural connectivity, both at the synaptic and circuit level, can lead to structural and functional abnormalities in brain, including gray matter reductions, cortical thinning, and white matter microstructural deficits. Excessive synaptic pruning, a self-activated natural process critical for efficient neural network refinement, appears to be overactivated in schizophrenia, contributing to cognitive deficits and psychotic symptoms. Molecular and genetic studies implicate complement-mediated microglial pruning, dysregulated neurodevelopmental genes (e.g., DISC1, C4, OPCML), and immune signaling pathways as mechanistic drivers of these synaptic and structural alterations. Translational models using CRISPR-edited human iPSC-derived neurons and cerebral organoids recapitulate schizophrenia-associated phenotypes, including impaired dendritic morphology, reduced synaptic density, neurotransmitter imbalance, and heightened sensitivity to environmental stressors. Multimodal neuroimaging, synaptic density tracers, and computational modeling reveal early biomarkers of pathological pruning and neurovascular dysregulation, offering potential for risk stratification and early intervention. Integrating molecular, structural, and functional findings highlights adolescence as a critical window of vulnerability and points toward preventive strategies, such as modulation of immune signaling, synaptic maintenance, and circuit-level interventions. Understanding schizophrenia as a neurodevelopmental disorder provides a better framework linking genetic, cellular, and structural changes in neurobiological system, offering potential avenues for personalized medicine and early targeted therapeutic approaches. This narrative Review provides insights into neuroplasticity mechanisms associated with the pathophysiology of schizophrenia as a neurobiological illness, particularly in the context of excessive synaptic pruning, recent advances, and challenges.
Waris et al. (Tue,) studied this question.