Patient iPSC-derived astrocytes with high polygenic risk for schizophrenia reveals a role for mitochondrial glutamate carrier SLC25A18

Abstract Schizophrenia is a highly heritable developmental disorder with often devastating effects on patients and their families. The causal mechanisms behind SCZ remain largely unknown, even after more than a century of research. Astrocytes are increasingly being associated with neuropsychiatric disorders including schizophrenia, yet have gained little attention in research. Therefore, in the current report, we investigate the role of astrocytes in schizophrenia by generating iPSC-derived astrocytes from 21 cases and 10 controls. Cases and controls were selected using a genetically informed strategy to increase statistical power of our study without a need for a priori knowledge of causal pathways. In addition, we selected patients with different genetic risk factors to test the generalization potential of our results. We show that neurons co-cultured with schizophrenia astrocytes have higher VGLUT/VGAT ratios than neurons co-cultured with controls astrocytes. Testing for transcriptional differences highlighted 10 genes that separated cases from controls. Of these, differences in SLC25A18 expression were most pronounced and is potentially driving the synaptic differences which we observed in our astrocyte-neuron co-cultures. Of note, SLC25A18 is encoded in a region that has been repeatedly associated with SCZ and its protein transports glutamate across the inner membrane of mitochondria. Our results confirm the involvement of astrocytes in schizophrenia pathology with a specific role for SLC25A18, and show that astroglia can indeed create neuronal abnormalities previously reported in SCZ (i.e. synaptic imbalance). More specifically, these findings support previous reports on the involvement of glutamate buffering by astrocytes and mitochondrial defects in the disease etiology of schizophrenia.