Hippocampal neurogenesis in schizophrenia: Strategies for harnessing neural stem cells

Schizophrenia is a severe psychiatric disorder characterized by positive, negative, and cognitive symptoms, with limited treatment efficacy beyond antipsychotics that mainly target dopaminergic pathways. Cognitive impairment and negative symptoms remain particularly resistant to current therapies, underscoring the need for novel interventions. Mounting evidence implicates hippocampal dysfunction and impaired neurogenesis in the pathophysiology of schizophrenia, highlighting hippocampal neural stem cells (hNSCs) as a promising therapeutic target. This review summarizes structural and functional hippocampal abnormalities in schizophrenia, including volume reduction, dysconnectivity, and hyperactivity linked to GABAergic deficits. It further discusses the disruption of adult hippocampal neurogenesis through genetic, environmental, and neurotransmitter-related mechanisms, positioning impaired hNSC function as a core feature of the disorder. The biology of hNSCs is outlined, emphasizing their capacity for self-renewal, differentiation, and integration within the dentate gyrus (DG). The potential therapeutic strategies are explored, including endogenous stimulation through pharmacological agents, lifestyle interventions, and epigenetic modulation, as well as exogenous transplantation approaches, although in vivo studies remain scarce. Finally, the review highlights the utility of stem cell models for mechanistic studies and drug discovery, offering valuable platforms to bridge the translational gap between genetic risk factors and clinical pathology. Altogether, this review underscores the significance of hNSCs in understanding schizophrenia’s complex biology and advancing therapeutic innovation. It provides a comprehensive framework for future investigations into neurogenesis-based interventions, offering novel directions toward improving cognitive and functional outcomes in patients.