Modeling schizophrenia using hiPSC neurons

By K. Brennand, A. Simone, J. Jou, Chelsea Gelboin-Burkhart, Ngoc N Tran, Sarah Sangar, Yan Li, Yangling Mu, Gong Chen, Diana Yu and 3 more. Nature, 2011

1,267 citations recorded by the source corpus.

Schizophrenia (SCZD) is a debilitating neurological disorder with a world-wide prevalence of 1%; there is a strong genetic component, with an estimated heritability of 80–85%. Although post-mortem studies have revealed reduced brain volume, cell size, spine density and abnormal neural distribution in the prefrontal cortex and hippocampus of SCZD brain tissue and neuropharmacological studies have implicated dopaminergic, glutamatergic and GABAergic activity in SCZD, the cell types affected in SCZD and the molecular mechanisms underlying the disease state remain unclear. To elucidate the cellular and molecular defects of SCZD, we directly reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons (Supplementary Fig. 1). SCZD hiPSC neurons showed diminished neuronal connectivity in conjunction with decreased neurite number, PSD95-protein levels and glutamate receptor expression. Gene expression profiles of SCZD hiPSC neurons identified altered expression of many components of the cyclic AMP and WNT signalling pathways. Key cellular and molecular elements of the SCZD phenotype were ameliorated following treatment of SCZD hiPSC neurons with the antipsychotic loxapine. To date, hiPSC neuronal pathology has only been demonstrated in diseases characterized by both the loss of function of a single gene product and rapid disease progression in early childhood. We now report hiPSC neuronal phenotypes and gene expression changes associated with SCZD, a complex genetic psychiatric disorder.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d4e5ecc93f4424ee438a397af3beda96e83828ad

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Citations in the corpus

The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016, positive): “, 2014), coupled with the application of advanced histological, imaging, molecular, cellular, and genomic techniques, has provided new insights into dynamic cellular and molecular processes in human neurodevelopment and dysfunction in a wide array of neurological and psychiatric disorders (Brennand ”
Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations (2011, neutral): “Individuals that are homozygous for this mutation have not been described, and the study of homozygous mutant cells may provide new insights into the pathogenesis of PD.”
Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia (2016, background): “334 Thus we further tested the impact of FURIN knockdown in human neural progenitor cells 335 (NPCs) capable of differentiating into mixed populations of post-mitotic neurons and astrocytes 336 (51, 52).”
Induced pluripotent stem cells: past, present, and future. (2012, positive): “…iPSCs can be used to recapitulate phenotypes of not only monogenic diseases but also late-onset polygenic diseases, such as Parkinson’s disease (Devine et al., 2011), Alzheimer’s disease (Israel et al., 2012; Yagi et al., 2011; Yahata et al., 2011), and schizophrenia (Brennand et al., 2011).”