G6PD deficiency in brain induces schizophrenia-like behaviors and synaptic dysfunction

Schizophrenia is a severe mental disorder characterized by aberrant brain development, influenced by genetic and environmental factors, with an incompletely understood etiology. Glucose-6-phosphate dehydrogenase (G6PD), a critical enzyme in the pentose phosphate pathway (PPP), facilitates NADPH production for biosynthesis and redox homeostasis. Recent studies suggests that PPP inhibition and consequent oxidative stress contribute to schizophrenia pathogenesis. While clinical investigations have proposed a link between G6PD deficiency and schizophrenia, the underlying biological mechanisms remain unestablished. We here demonstrate that brain-specific G6PD knockout induces schizophrenia-like behaviors in mice, establishing a direct association between G6PD deficiency and schizophrenia. Proteomic analysis revealed aberrant synaptic protein expression in the knockout mice. These mice also exhibited synaptic impairments, including reduced presynaptic vesicles and diminished dendritic spines. Our findings suggest that G6PD deficiency disrupts synaptic homeostasis, contributing to schizophrenia-like behaviors. Our study provides novel insights into the molecular mechanisms of schizophrenia, identifying G6PD as an important regulator of synaptic function and a potential therapeutic target.