Using mouse transgenic and human stem cell technologies to model genetic mutations associated with schizophrenia and autism

Abstract

Solid progress has occurred over the last decade in our understanding of the molecular genetic basis of neurodevelopmental disorders, and of schizophrenia and autism in particular. Although the genetic architecture of both disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed in vivo and in vitro technologies to be refined to model specific high-penetrant genetic loci involved in both disorders. Using the DISC1/NDE1 and CYFIP1/EIF4E loci as exemplars, we explore the opportunities and challenges of using animal models and human-induced pluripotent stem cell technologies to further understand/treat and potentially reverse the worst consequences of these debilitating disorders.This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

“…Animal models of disruption can be obtained for almost all human genes [119]. The mouse genome is almost as well characterized as the human and mouse models are cost effective, straightforward to produce, and allow investigation at the molecular, cellular, circuit, and behavioral levels [119]. The disadvantage of rat models is the cost of maintenance and it is not balanced by obvious advantages of rat models.…”

“…The disadvantage of rat models is the cost of maintenance and it is not balanced by obvious advantages of rat models. The high-throughput and low-cost models involve zebrafish (Danio rerio) and fruit fly (Drosophila melanogaster), but obviously these systems are not applicable for reproducing more complex human behaviors [119]. It should be stressed that there are a number of shortcomings of usage of genetic animal models to study neuropsychiatric disorders.…”

“…It should be stressed that there are a number of shortcomings of usage of genetic animal models to study neuropsychiatric disorders. Interpreting SZ-like phenotypes in mice, including complex symptoms such as paranoia and delusional beliefs, is challenging: they can only be inferred indirectly from disordered mice behavior, a major limitation of modelling SZ in animals [119].…”

Development of two-photon polymerised scaffolds for optical interrogation and neurite guidance of human iPSC-derived cortical neuronal networks

“…Developments with iPSC-derived neural cultures are advancing rapidly, however a majority have so far focused on deriving two dimensional planar cultures featuring a single subtype of neural cells, and a limited number of functional endpoints. 15,16 In addition, a high variability of derived neuronal cell types and a lack of defined network architecture makes deriving conclusions from the analysis potentially problematic.…”

Of mice and mental health: facilitating dialogue and seeing further

“…By modelling potential causes of schizophrenia-genetic and environmental, including earlylife experiences-and measuring specific psychological processes, such as working memory, that have been shown to be impaired in patients with schizophrenia using translational tasks, it is possible to use the array of circuit-mapping and causal manipulations in rodents to provide insights into the clinical condition. St Clair & Johnstone [27] review the advantages of taking this modelling further, to the level of stem cells and brain organoids, to identify potential treatments for schizophrenia and autism at the pharmacological and molecular levels.…”