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.
Hereditary factors contribute significantly to the development of schizophrenia. However, despite many years of research, the genetic architecture and mechanisms of the participation of genetic factors in the development of schizophrenia are not well understood. Genome-wide analyzes of genetic associations in various non-coding regions of the genome, including gene enhancers, revealed many loci associated with an increased risk of schizophrenia. In the course of the analysis of the spatial structure of the genome, we revealed the interaction of these enhancers with the promoter regions of genes involved in the metabolism of neurons. To study in more detail the functions of these genes and the participation of enhancers in their regulation, we obtained plasmid and lentiviral constructs of a functionally active transcription repressor based on the CRISPR / SpyCas9 system, as well as the endonuclease system. The use of these constructs in studies of the functions of enhancers and genes associated with the metabolism and regulation of gene expression in neurons is discussed.
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