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’.

Highlights

  • Schizophrenia (SCZ) and autism (ASD) are two of the most important neurodevelopmental disorders encountered in routine clinical psychiatric practice

  • Chromosome 15q11.2 copy number variants (CNVs) have emerged as prominent risk factors for various neuropsychiatric disorders, including SCZ, autistic spectrum disorder and intellectual disability [147]. 15q11.2 microdeletion (15q11.2 del) was identified as one of the most frequent CNVs associated with increased risk for SCZ [22], a finding subsequently confirmed in additional cohorts [114,148,149]. 15q CNVs are not as penetrant as other recurrent CNVs associated with neurodevelopmental disorders

  • They showed that human-induced pluripotent stem cell (hiPSC)-derived neural progenitor cells carrying 15q11.2 microdeletions exhibited deficits in adherens junctions and apical polarity resulting from haploinsufficiency of CYFIP1 [47]

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Summary

Introduction

Schizophrenia (SCZ) and autism (ASD) are two of the most important neurodevelopmental disorders encountered in routine clinical psychiatric practice. Both are diagnosed on the basis of clinical history, symptoms and behaviour. Ages of clinical presentation of SCZ and ASD are normally early adult life and early infancy, respectively, both have at least in part neurodevelopmental origins, namely antecedents affecting brain development, and, in turn, predisposition to one or both disorders can occur at any point in the life cycle probably from conception onwards. Perhaps, the most intriguing finding to emerge from epidemiological studies is that SCZ and ASD appear to share a remarkable number of environmental risk factors [4,5]. A similar pattern of overlapping genetic risk profiles for SCZ and ASD will be discussed below

Familiarity
Modelling: from mice to men
Nuclear distribution E homologue 1
Cytoplasmic fragile X mental retardation 1– interacting protein
Eukaryotic translation initiation factor 4E 8
Conclusion
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Findings
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