Abstract
Schizophrenia (SZ) is a prevalent functional psychosis characterized by clinical behavioural symptoms and underlying abnormalities in brain function. Genome-wide association studies (GWAS) of schizophrenia have revealed many loci that do not directly identify processes disturbed in the disease. For this reason, the development of cellular models containing SZ-associated variations has become a focus in the post-GWAS research era. The application of revolutionary clustered regularly interspaced palindromic repeats CRISPR/Cas9 gene-editing tools, along with recently developed technologies for cultivating brain organoids in vitro, have opened new perspectives for the construction of these models. In general, cellular models are intended to unravel particular biological phenomena. They can provide the missing link between schizophrenia-related phenotypic features (such as transcriptional dysregulation, oxidative stress and synaptic dysregulation) and data from pathomorphological, electrophysiological and behavioural studies. The objectives of this review are the systematization and classification of cellular models of schizophrenia, based on their complexity and validity for understanding schizophrenia-related phenotypes.
Highlights
Schizophrenia (SZ) is a severe mental disease affecting 1% of the population globally
The genetic architecture of SZ includes rare gene mutations, copy number variations (CNVs), deletions (e.g., 22q11.2 and 3q29) and chromosome translocations that contribute to the risk of SZ
Genome-wide association studies (GWAS)-guided investigation of in vitro models will advance our knowledge of the pathogenic molecular mechanisms of SZ
Summary
Schizophrenia (SZ) is a severe mental disease affecting 1% of the population globally. There are several hypotheses to explain the origin of SZ It may result from neurotransmitter misbalances, as suggested in the dopamine, glutamate and gamma-aminobutyric acid (GABA) hypotheses, or from changes in inflammation-related biochemical pathways (the kynurenic acid hypothesis). Both environmental and genetic factors are involved in the pathogenesis of SZ, the latter playing a pivotal role in disease risk; the heritability of SZ is estimated at 70 to 85% [1,2]. We describe the most important cellular models used in basic research and drug discovery to investigate the molecular mechanisms associated with SZ at the cellular, biochemical and genetic levels. Particular attention is given to CRISPR/Cas systems as effective instruments to manipulate the cellular models
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