Modeling neurodevelopmental disorders using human neurons

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The cellular and molecular mechanisms of neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The unavailability of live patient neurons for research, however, has represented a major obstacle in the elucidation of the disease etiologies. Recently, the development of induced pluripotent stem cell (iPSC) technology allows for the generation of human neurons from somatic cells of patients. We review ongoing studies using iPSCs as an approach to model neurodevelopmental disorders, the promise and caveats of this technique and its potential for drug screening. The reproducible findings of relevant phenotypes in Rett syndrome iPSC-derived neurons suggest that iPSC technology offers a novel and unique opportunity for the understanding of and the development of therapeutics for other autism spectrum disorders.

Highlights

► iPSCs as a useful model for neurodevelopmental diseases. ► An increasing number of neurodevelopmental diseases modeled using iPSC approach. ► Disease-specific iPSC-derived neurons mimic relevant neuronal phenotypes. ► Successfully modeling Rett Syndrome using iPSCs. ► Using iPSC systems to develop drug-screening platforms.

Introduction

The limited potential of neuronal samples from post-mortem brains and the inability to isolate populations of neurons from living subjects has blocked progress toward understanding the cellular and molecular mechanisms behind several neurodevelopmental disorders. Studies of postmortem tissue are problematic in developmental disorders as disease onset usually precedes death by decades. Moreover, frozen tissue sections are of limited use for studying cellular physiology and neural networks. Peripheral tissues, such as blood, are not suitable for relevant biological experiments since they are not the target tissue. Mathematical or computational models are also restricted by nature. Brain imaging allows you to study circuitries at a low magnification and does not reveal details of short circuitries in the brain. Finally, animal models often do not recapitulate complex human diseases, and have been particularly problematic in the case of human neurodevelopmental disease such as autism. Thus, the field lacks a human model that could provide unlimited supplies of neurons so experiments can be performed in controlled situations.

Genetic reprogramming provides a complementary model as it allows the genomes of human individuals afflicted with neurodevelopmental diseases to be captured in a pluripotent stem cell line. Reprogramming of somatic cells to a pluripotent state by overexpression of specific genes has been accomplished using mouse and human cells [1, 2••]. These reprogrammed cell types, named induced pluripotent stem cells (iPSCs) can be derived from cells isolated from peripheral tissues of normal individuals or people affected from several conditions [3]. Isogenic pluripotent cells are attractive not only for their potential therapeutic use with lower risk of immune rejection, but also for their prospects to further understanding of complex diseases with heritable and sporadic conditions [4, 5]. iPSCs can then be differentiated to human neurons to evaluate whether the captured genome alters cellular phenotypes in a similar manner as predicted by the clinical data or other mechanistic models. Although iPSCs have been generated for several neurological diseases the demonstration of disease-specific pathogenesis and phenotypic rescue in relevant cell types is a current challenge in the field, with only a handful proof-of-principle examples to date [6]. Nonetheless, the examples reflect the potential that this new model brings to disease modeling.

Section snippets

Considerations about iPSCs as a model for neurodevelopmental diseases

As with other models, the iPSC system also has important limitations. Cells in culture represent a research artifact. Thus, it is possible that important signaling information is missing or overstimulated in the system, masking potential cellular phenotypes or creating artificial ones. The discrimination between what is real and truly important in vivo will probably depend on validations coming from other models. Another challenge is the derivation of relevant neuronal subtypes. Specific

Modeling neurodevelopmental diseases in a dish

A few years after the success of somatic cell reprogramming was reported in 2006, iPSC technology has been extensively used to model several neurodevelopmental diseases including a monogenic form of autism spectrum disorders (ASDs). Rett syndrome (RTT) [11••, 12, 13, 15], sporadic form of Schizophrenia (SCZD) [16], fragile X syndrome (FXS) [17], and Timothy syndrome (TS) [18••]. These studies were able to demonstrate that such disease-specific iPSC-derived neurons elegantly recapitulated

Modeling Rett syndrome with iPSCs

We recently demonstrated the utility of induced pluripotent stem cells to investigate the functional consequences of mutations in the gene encoding the Methyl CpG binding protein-2 (MeCP2) on neurons from RTT patients, a syndromic form of ASD [11]. RTT patients appear to develop normally for up to 6–18 months, after which they enter a period of regression characterized by deceleration of head growth and loss of acquired motor and language skills. Patients often develop autistic behaviors,

Using human neurons as a drug-screening platform

Our studies performed in RTT highlighted the potential of iPSC models in toxicology and drug screening. Even better, the IGF1 overcorrection observed in some RTT neurons [11••] indicate that the iPSC technology not only can recapitulate some aspects of a genetic disease but also can be used to better design and anticipate results from translational medicine. This cellular model has the potential to lead to the discovery of new compounds to treat different neurodevelopmental diseases.

Conclusion

The iPSC strategy is a novel and complementary approach to model neurodevelopmental diseases. Although this technology is still in its early stage, it potentially demonstrated the ability to recapitulate relevant neuronal defects of those diseases. This model has the capacity to unify data generated from brain imaging, animal work, and genetics, generating downstream hypotheses that could be tested in well-controlled experiments in the relevant cell types. As several neurodevelopmental

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The work was supported by grants from the California Institute for Regenerative Medicine (CIRM) TR2-01814, the National Institutes of Health through the NIH Director's New Innovator Award Program, 1-DP2-OD006495-01, 1R21MH093954 from NIMH, P01 HD33113 and NS22343 from NIH, the Royal Thai Government Scholarship to T.C., the NIH predoctoral training grant T32 GM008666 to A.A and the Emerald Foundation. We would like to thank members of the Muotri laboratory for critical comments on the

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