| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2530001 | Current Opinion in Pharmacology | 2011 | 7 Pages |
Identifying the molecular and cellular basis of complex neuropsychiatric disorders (cNPDs) has been limited by the inaccessibility of central neurons, variability within broad diagnostic classifications, and the interplay of genetic and environmental factors. Recent work utilizing neuronally differentiated human induced pluripotent stem cells (hiPSCs) from Mendelian and polygenic cNPDs is beginning to illuminate neuritic, synaptic or cell body variations accompanied by specific gene or protein expression alterations largely mimicking known pathology. In some cases, phenotypes have only emerged after application of cellular stress or long duration of differentiation. Pathological and cellular expression features are fully or partially responsive to pharmacological treatment highlighting the potential utility of differentiated hiPSCs for discovery of personalized therapeutics and for identifying pathogenetically relevant targets in subgroups of patients within a broad syndromic classification. Because of the inherent variability in developing and differentiating hiPSC lines and the multiple comparisons implicit in ‘omics’ technologies, rigorous algorithms for assuring statistical significance and independent confirmation of results, will be required for robust modeling of cNPDs.
► Differentiated iPS lines from neuropsychiatric disease show neuronal abnormalities. ► Neuritic, synaptic and gene expression defects arise in culture and after cellular stress. ► Drug treatments can largely reverse neuronal abnormalities in iPS cultures. ► Variability and cellular instability combined with ‘omics’ technologies raise challenges. ► A roadmap for validating models and finding personalized therapies is proposed.
