Schizophrenia (SZ) is a debilitating psychiatric disorder. While 1.1% of the population suffers from SZ, the molecular mechanisms underlying the disease state remain unclear. Though its characteristic symptoms typically appear late in adolescence, SZ is believed to result from abnormal neurodevelopmental processes that begin years before the onset of symptoms. We previously reprogrammed fibroblasts from SZ patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neural progenitor cells (NPCs) and neurons. We and others have found that SZ hiPSC NPCs show evidence of aberrant migration 1, increased oxidative stress 1-3, perturbed responses to environmental stressors 4, while SZ hiPSC neurons exhibit decreased neurite number 5 reduced synaptic maturation 2,6-8 and reduced synaptic activity 6,8. Although hiPSC-derived neurons most resemble human fetal brain tissue9-11 and presumably best model disease predisposition, there has been good concordance between hiPSC studies and reports of aberrant migration 12,13, reduced neurite outgrowth 14,15, abnormal axon targeting 16 and impaired synaptic activity 17-21 in mouse models of SZ. We believe that hiPSC neural cells are best used to study the developmental effects that contribute to SZ risk.
1. Brennand, K., et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry (2014).
2. Robicsek, O., et al. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol Psychiatry (2013).
3. Paulsen, B.D., et al. Altered oxygen metabolism associated to neurogenesis of induced pluripotent stem cells derived from a schizophrenic patient. Cell Transplant (2011).
4. Hashimoto-Torii, K., et al. Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron 82, 560-572 (2014).
5. Brennand, K.J., et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature (2011).
6. Yu, D.X., et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports 2, 295-310 (2014).
7. Wen, Z., et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature (2014).
8. Zhang, L., Song, X., Mohri, Y. & Qiao, L. Role pf Inflammation and Tumor Microenvironment in the Development of Gastrointestinal Cancers: What Induced Pluripotent Stem Cells Can Do? Current stem cell research & therapy (2014).
9. Brennand, K.J., et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular psychiatry (2014).
10. Mariani, J., et al. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc Natl Acad Sci U S A 109, 12770-12775 (2012).
11. Nicholas, C.R., et al. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12, 573-586 (2013).
12. Meechan, D.W., Tucker, E.S., Maynard, T.M. & LaMantia, A.S. Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome. Proc Natl Acad Sci U S A 106, 16434-16445 (2009).
13. Yoon, K.J., et al. Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell 15, 79-91 (2014).
14. Kvajo, M., et al. A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci U S A 105, 7076-7081 (2008).
15. Krivosheya, D., et al. ErbB4-neuregulin signaling modulates synapse development and dendritic arborization through distinct mechanisms. J Biol Chem 283, 32944-32956 (2008).
16. Faulkner, R.L., et al. Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc Natl Acad Sci U S A 105, 14157- 14162 (2008).
17. Kwon, O.B., Longart, M., Vullhorst, D., Hoffman, D.A. & Buonanno, A. Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. J Neurosci 25, 9378-9383 (2005).
18. Woo, R.S., et al. Neuregulin-1 enhances depolarization-induced GABA release. Neuron 54, 599-610 (2007).
19. Chun, S., et al. Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models. Science 344, 1178-1182 (2014).
20. Maher, B.J. & LoTurco, J.J. Disrupted-in-schizophrenia (DISC1) functions presynaptically at glutamatergic synapses. PLoS One 7, e34053 (2012).
21. Niwa, M., et al. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron 65, 480-489 (2010).