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

Abstract

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.

Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance

“…Gene set enrichment analyses suggested involvement of pathways related to WNT signaling and forebrain development. Dysregulation of both of these pathways has been consistently observed in previous studies of SCZ using hiPSCs 16,[39][40][41] . In addition, we found that NPC DEGs correlated with neuronal DEGs, which is also consistent with previous findings 10 .…”

Inhibition of AKT Signaling Alters βIV Spectrin Distribution at the AIS and Increases Neuronal Excitability

“…While a growing body of research suggests that alterations in the AKT/GSK3 pathway activity is a common feature of many neuropsychiatric and neurodegenerative disorders ( Emamian et al, 2004 ; Emamian, 2012 ; Chen et al, 2015 ; McGuire et al, 2017 ; Stertz et al, 2020 ), studying the consequences of this purported dysfunction is difficult, considering the relatively quick activity of phosphatases post-mortem ( Li et al, 2005 ) and the paucity of available brains. In contrast, primary hippocampal neuronal cultures are an excellent in vitro model of basic neurobiological functions.…”

“…AKT is activated through phosphorylation by PI3K, while GSK3 is a constitutively active kinase whose activity is decreased upon phosphorylation by AKT ( Sutherland et al, 1993 ; Jensen et al, 2007 ). Disruption of the AKT/GSK3 pathway has been shown to be a risk factor for neuropsychiatric and neurodegenerative disorders ( Crofton et al, 2017 ; Hsu et al, 2017 ; Scala et al, 2018 ; Stertz et al, 2020 ). Wee1 kinase is a complex enzyme that is regulated and degraded by GSK3 through ubiquitination ( Watanabe et al, 2004 ; Li et al, 2012 ; Penas et al, 2015 ).…”

The Molecular Mechanism of Multiple Organ Dysfunction and Targeted Intervention of COVID-19 Based on Time-Order Transcriptomic Analysis

“…The gene expression profiles of five organs on days 1, 2, 4, 6, 8, and 14 after SARS-CoV-2 infection were compared with the normal control group (day 0) to identify the differences in gene expression in each organ, and all the differences in gene expression were combined to obtain the DEGs in each organ for further analysis. DEGs were screened using the DEseq2 function in R (version 3.6.3) ( 23 , 24 ).…”