PHGDH inhibition interferes with neuron-astrocyte interactions during neural maturation

Neurodevelopmental disorders stem from multiple synergistic deficiencies within multifaceted biological networks. Neuronal differentiation depends on complex regulatory machinery, with neuron-astrocyte interactions being a central player. D -serine is a neuromodulatory amino acid that is pivotal to neuron-astrocyte communication. Glucose is the initial precursor for D -serine production; one of the downstream enzymes of this production pathway, 3-phosphoglycerate dehydrogenase (PHGDH), has shown differential expression in postmortem brain tissue and neuronal cells derived from patients with schizophrenia. In this study, we integrated pluripotent stem cell differentiation, PHGDH inhibition, and proteomics/metabolomics to investigate the biological mechanisms involved in neural dysfunction at the early stages of neurodevelopment, which are hypothesized to result in synaptic deficits. These analyses showed that, while neurons and astrocytes both exhibited phenotypic alterations after exposure to a PHGDH inhibitor, neurons were more sensitive to its effect. When inhibited during differentiation, neurons presented dysfunctions in cell death and axonal migration pathways, likely caused by dysregulation in energy metabolism. Our in vitro findings suggest the importance of PHGDH in the context of neural maturation and connectivity, adding one more puzzle piece to the neurodevelopmental biological network.