Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 46; no. 3; pp. 673 - 682
• Main Authors: Stertz, Laura, Di Re, Jessica, Pei, Guangsheng, Fries, Gabriel R., Mendez, Emily, Li, Shenglan, Smith-Callahan, Laura, Raventos, Henriette, Tipo, Jerricho, Cherukuru, Rohan, Zhao, Zhongming, Liu, Ying, Jia, Peilin, Laezza, Fernanda, Walss-Bass, Consuelo
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.02.2021; Springer International Publishing
• Subjects: 1-Phosphatidylinositol 3-kinase; Cell lines; Enzyme inhibitors; Fibroblast growth factors; Gene expression; Genomics; Glucocorticoids; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - genetics; Humans; Kinases; Mental disorders; Neural Stem Cells; Neurons; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Pluripotency; Ribonucleic acid; Risk factors; RNA; Schizophrenia; Schizophrenia - genetics; Signal transduction; Stem cells; Transcriptomes; Tubulin
• DOI: 10.1038/s41386-020-00924-0
• ISSN: 0893-133X; 1740-634X

Human-induced pluripotent stem cells (hiPSCs) allow for the establishment of brain cellular models of psychiatric disorders that account for a patient’s genetic background. Here, we conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology. Transcriptome from these cells was obtained using Illumina HiSeq 2500, and differential expression analyses were performed using DESeq2 (|fold change|>1.5 and false discovery rate < 0.3), in patients compared to controls. We identified 454 differentially expressed genes in hiPSC-derived neurons, enriched in pathways including phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3) signaling, with serum-glucocorticoid kinase 1 (SGK1), an inhibitor of glycogen synthase kinase 3β, as part of this pathway. We further found that pharmacological inhibition of downstream effectors of the PI3K/GSK3 pathway, SGK1 and GSK3, induced alterations in levels of neurite markers βIII tubulin and fibroblast growth factor 12, with differential effects in patients compared to controls. While demonstrating the utility of hiPSCs derived from multiplex families to identify significant cell-specific gene network alterations in SCZ, these studies support a role for disruption of PI3K/GSK3 signaling as a risk factor for SCZ.