Modeling psychiatric disorders through reprogramming

Abstract

Psychiatric disorders, including autism spectrum disorders and schizophrenia, are extremely heritable complex genetic neurodevelopmental disorders. It is now possible to directly reprogram fibroblasts from psychiatric patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiate these disorder-specific hiPSCs into neurons. This means that researchers can generate nearly limitless quantities of live human neurons with genetic backgrounds that are known to result in psychiatric disorders, without knowing which genes are interacting to produce the disease state in each patient. With these new human-cell-based models, scientists can investigate the precise cell types that are affected in these disorders and elucidate the cellular and molecular defects that contribute to disease initiation and progression. Here, we present a short review of experiments using hiPSCs and other sophisticated in vitro approaches to study the pathways underlying psychiatric disorders.

Fig. 1.

Cellular phenotypes of RTT. (A) hiPSC-derived neurons from RTT patients show decreased soma size. *P<0.0001, Student’s t-test. Adapted from Cheung et al. (Cheung et al., 2011), with permission. (B) RTT-hiPSC-derived neurons have reduced density of excitatory synapses along dendrites compared with neurons derived from healthy controls. The staining shows that hiPSC-derived neurons from RTT patients have fewer VGLUT1-positive glutamatergic synaptic puncta interspersed along MAP2-positive dendrites. (C) Tracking fluorescence intensity changes representing intracellular Ca²⁺ fluctuations provides evidence of reduced synaptic activity in RTT-hiPSC-derived neurons relative to controls. B and C are adapted from Marchetto et al. (Marchetto et al., 2010), with permission. ROI, region of interest; WT, wild type. Scale bar: 5 μm.

Fig. 2.

Cellular phenotype of SCZD. Rabies virus transmission between neurons can be used to assay neuronal connectivity. SCZD-hiPSC-derived neurons show decreased transmission of a genetically engineered rabies virus designed specifically to indicate monosynaptic neuronal connectivity (Rabies-EnvAΔG-RFP). Adapted from Brennand et al. (Brennand et al., 2011), with permission. LV-SYNP-HTG, lentivirus expressing a fusion protein comprising histone 2B and green fluorescent protein, TVA and elements of the synapsin (SYN) promoter; used to label neurons for microscopic analysis. Scale bar: 80 μm.