Progress of Induced Pluripotent Stem Cell Technologies to Understand Genetic Epilepsy

Abstract

The study of the pathomechanisms by which gene mutations lead to neurological diseases has benefit from several cellular and animal models. Recently, induced Pluripotent Stem Cell (iPSC) technologies have made possible the access to human neurons to study nervous system disease-related mechanisms, and are at the forefront of the research into neurological diseases. In this review, we will focalize upon genetic epilepsy, and summarize the most recent studies in which iPSC-based technologies were used to gain insight on the molecular bases of epilepsies. Moreover, we discuss the latest advancements in epilepsy cell modeling. At the two dimensional (2D) level, single-cell models of iPSC-derived neurons lead to a mature neuronal phenotype, and now allow a reliable investigation of synaptic transmission and plasticity. In addition, functional characterization of cerebral organoids enlightens neuronal network dynamics in a three-dimensional (3D) structure. Finally, we discuss the use of iPSCs as the cutting-edge technology for cell therapy in epilepsy.

Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms

“…Epilepsy-associated genes encode for ion channel and synaptic proteins, cell adhesion molecules, signaling proteins, and transcription factors. However, possible mutations in such different genes that can lead to epileptic seizures in most cases remain unclear [7][8][9]. The role of epigenetic modifications has been actively studied recently in the development of epilepsy [10][11][12][13][14].…”

“…Our previous studies showed [31] that in the Russian population (East Slavic ethnic group, the sample of individuals from 17 to 90 years old) UPS29 was represented by seven alleles, which differed not only in the number of repeats (6,8,9,10,14,17, and 24 ones) but also in combination of repeated units, as well as in the presence of deletions and/or single-nucleotide polymorphisms (SNPs) in DNA flanking minisatellite ( Figure 1 and Figure S2, Table S3). In the studied cohort, the allele of 17 repeats was predominant (91.5%), but the frequencies of other alleles were lower (from 0.3% to 4.4%).…”

Cerebral Organoids—Challenges to Establish a Brain Prototype

“…Several attempts were made to fuse spheroids or organoids of different cellular compositions to model more complex 3D brain structures (Birey et al 2017; Bagley et al, 2017) [ 51 , 114 ]. For example, Birey et al (2017) fused oligodendrocytes with an organoid consisting of GABAergic neurons and an organoid consisting of glutamatergic neurons and astrocytes [ 51 ].…”

“…Several attempts were made to fuse spheroids or organoids of different cellular compositions to model more complex 3D brain structures (Birey et al 2017; Bagley et al, 2017) [ 51 , 114 ]. For example, Birey et al (2017) fused oligodendrocytes with an organoid consisting of GABAergic neurons and an organoid consisting of glutamatergic neurons and astrocytes [ 51 ]. Using these conglomerate structures, the authors demonstrated the migration of GABA neurons from the ventral to the dorsal forebrain, their integration, and the formation of cortical nerve chains.…”

“…Knockout of the CDK5RAP2 gene in healthy iPSCs resulted in a similar phenotype in organoids. In another study, brain organoids were established from iPSCs of patients with genetically determined epilepsy [ 51 ], making it possible to study the electrophysiological activity of “diseased” neurons. Birey et al (2017) created organoids from iPSCs with point mutations in the CACNA1C gene, causing Timothy syndrome and associated with a nervous system disorder [ 52 ].…”