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Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont KG, Kim HJ, Topol A, Ladran I, Abdelrahim M, Matikainen-Ankney B, Chao SH, Mrksich M, Rakic P, Fang G, Zhang B, Yates JR, Gage FH. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry . 2014 Apr 1 ; PubMed Abstract

Comments on Paper and Primary News
Comment by:  Christopher Ross
Submitted 9 April 2014 Posted 9 April 2014

Schizophrenia Redux?
Sometimes a longer follow-up paper can be just as significant as an initial, shorter paper in a higher-impact journal. This may be the case with the recent paper by Brennand et al. in Molecular Psychiatry, which follows from the initial study of Brennand et al. (Brennand et al., 2011) in Nature. The second paper has a great deal of new data, but more strikingly, has two provocative hypothesizes about iPS cell models of schizophrenia.

The advent of human iPS cell technology has the potential to transform research into brain diseases such as schizophrenia. Ongoing studies of iPS cell models of neurodegenerative diseases illustrate the potential. For instance, in studies from the HD iPS cell consortium, we find that HD iPS cells show CAG-expansion length-dependent cell toxicity, which can be rescued with BDNF (HD iPS Cell Consortium, 2012), and in our ongoing studies, with small molecules, indicating utility for both pathogenesis and experimental...  Read more

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Primary News: Neural Progenitor Cells Model Aspects of Schizophrenia

Comment by:  Nao GamoAkira Sawa (SRF Advisor)
Submitted 7 May 2014 Posted 7 May 2014

This study introduces a novel use of neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) to address mechanisms that may possibly underlie a predisposition to schizophrenia. Brennand et al. (2014) generated hiPSC-derived NPCs from patients with schizophrenia and control subjects. These NPCs, as well as six-week-old neurons differentiated from them, showed gene expression profiles similar to those of the fetal forebrain. Thus, these cells were used to address early disease etiology, in particular, focusing on mechanisms related to disruptions in prefrontal cortical development. Interestingly, the researchers found overlap in gene signatures between the six-week-old neurons and NPCs from patients, raising the possibility that disease predisposition may already be established at the NPC stage.

Particularly striking is the reduced migration of schizophrenia NPCs relative to control NPCs as they differentiated into neurons. This reduced migration may be due to schizophrenia NPCs remaining in a proliferative state before differentiating, as...  Read more

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Primary News: Neural Progenitor Cells Model Aspects of Schizophrenia

Comment by:  Bryan MowrySamuel Nayler
Submitted 29 May 2014 Posted 29 May 2014

In a recent follow-up to their 2011 paper, Brennand et al. report considerable progress toward generation of a defined neuronal population generated from patient-derived induced pluripotent stem (iPS) cells. The advent of the iPS cell has been somewhat Promethean in that pluripotent stem cells are now a commonly utilized laboratory tool for disease modeling. While marked progress has occurred on a number of fronts, it is still not known to what degree stem cell-derived neurons truly resemble mature neurons that exist in the brain of a living human. Moreover, it is an open question what these cells can tell us about the onset of a clinically heterogeneous, polygenic disease such as schizophrenia.

Using gene expression analysis, Brennand et al. compare their samples to a developmental spectrum of samples from the Allen Brain Atlas to show that their iPSC-derived neurons most closely resemble early fetal forebrain neurons. This may provide precisely the model system that will allow researchers to validate the neurodevelopmental theory of schizophrenia, provided early...  Read more

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