You are hereOctober 15, 2014 | ESCs/iPSCs
iPSC Model Links Neuropsychiatric-associated Genetic Defects to Synaptic Deficits
Review of “Synaptic dysregulation in a human iPS cell model of mental disorders” from Nature by Stuart P. Atkinson
Research in the neuropsychiatric field has pointed to altered structural and functional connectivity of neurons as a major cause of many disorders , but links between genetic and synaptic defects are not well understood. Researchers from the laboratory of Guo-li Ming (Johns Hopkins University School of Medicine, Baltimore, USA) have attempted to uncover such links through the generation of induced pluripotent stem cells (iPSCs) from patients with a mutation in the Disrupted in Schizophrenia 1 (DISC1) gene, which is linked to major psychiatric disorders [2, 3]. Their findings, published in Nature, suggest that not only do mutations in DISC1 lead to synaptic deficits in iPSC-derived forebrain neurons, but that they also lead to the dysregulation of the expression of many genes related to synapses and which are associated with psychiatric disorders .
The study utilised iPSCs generated via episomal non-integrative methods, which were differentiated (alongside control iPSCs) into forebrain-specific human neural progenitor cells (hNPCs) and then into MAP2AB+ neurons. These neurons were mainly glutamatergic (VGLUT1+ or -CAMKII+) and expressed various cortical layer markers. Assessment of DISC1 gene expression found similar mRNA expression of the common exon 2, although neurons from patients with the DISC1 mutation only expressed 20% of the total DISC1 protein detected in control neurons. Furthermore, mutant DISC1 formed aggregates with and depleted wild type DISC1 leading to a significant and dose-dependent decrease in wild type DISC1 protein.
Neuron development studies found no consistent morphological differences at 4 weeks after differentiation, but the density of synaptic boutons, part of the chemical synapse, were significantly reduced in DISC1 mutants between 4 and 6 weeks, as were the frequency of excitatory spontaneous synaptic currents (SSCs), suggesting a presynaptic defect in synaptic release. Interestingly, correction of the DISC1 mutation reversed these deficits, while artificial introduction of the DISC1 mutation into wild type cells produced the previously observed mutant phenotype, which together established a causal role for the DISC1 mutation in synaptic defects of human neurons.
RNA-Sequencing of 4-week-old forebrain neurons found a large number of differentially expressed genes between control and mutant neurons, with the top three significantly enriched categories from gene ontology analysis being ‘synaptic transmission’, ‘nervous system development’ and ‘dendritic spine’. Additionally a large number DISC1-interacting proteins genes were also differentially expressed, while 89 genes associated with schizophrenia, bipolar disorder, depression and mental disorders also showed significant variations. Further in depth analysis identified varying changes in the levels of multiple presynaptic proteins, post-synaptically localized proteins and several transporters, whose complex interactions may lead to the synaptic deficits observed. Of notable interest was the mutation-associated decrease in the transcription factor MEF2C, understood to restrict glutamatergic synapse numbers  and to decrease frequency, but not amplitude of spontaneous synaptic currents in mice , resembling that observed in DISC1 mutant human neurons.
This elegant study has, for the first time, linked a specific genetic defect linked to psychiatric disorders to deficits in neural function. The model system generated by the laboratory will enable further detailed analysis and will advance our understanding in this field as well as allow the screening of therapeutic compounds to reverse/correct synaptic defects. Interestingly, DISC1 mutant phenotypes overlap with those seen in idiopathic schizophrenia patient iPS cells [7-9] suggesting a common disease mechanism, and that some therapeutically relevant compounds discovered may be utile across a range of diseases/disorders.
- Weinberger DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44:660-669.
- Sachs NA, Sawa A, Holmes SE, et al. A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry 2005;10:758-764.
- Thomson PA, Malavasi EL, Grunewald E, et al. DISC1 genetics, biology and psychiatric illness. Front Biol (Beijing) 2013;8:1-31.
- Wen Z, Nguyen HN, Guo Z, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 2014;
- Flavell SW, Cowan CW, Kim TK, et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 2006;311:1008-1012.
- Barbosa AC, Kim MS, Ertunc M, et al. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proceedings of the National Academy of Sciences of the United States of America 2008;105:9391-9396.
- Brennand KJ, Simone A, Jou J, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011;473:221-225.
- Yu DX, Di Giorgio FP, Yao J, et al. Modeling hippocampal neurogenesis using human pluripotent stem cells. Stem Cell Reports 2014;2:295-310.
- Brennand K, Savas JN, Kim Y, et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 2014.