Studying and modulating schizophrenia-associated dysfunctions of oligodendrocytes with patient-specific cell systems

Abstract

Postmortem studies in patients with schizophrenia (SCZ) have revealed deficits in myelination, abnormalities in myelin gene expression and altered numbers of oligodendrocytes in the brain. However, gaining mechanistic insight into oligodendrocyte (OL) dysfunction and its contribution to SCZ has been challenging because of technical hurdles. The advent of individual patient-derived human-induced pluripotent stem cells (hiPSCs), combined with the generation of in principle any neuronal and glial cell type, including OLs and oligodendrocyte precursor cells (OPCs), holds great potential for understanding the molecular basis of the aetiopathogenesis of genetically complex psychiatric diseases such as SCZ and could pave the way towards personalized medicine. The development of neuronal and glial co-culture systems now appears to enable the in vitro study of SCZ-relevant neurobiological endophenotypes, including OL dysfunction and myelination, with unprecedented construct validity. Nonetheless, the meaningful stratification of patients before the subsequent functional analyses of patient-derived cell systems still represents an important bottleneck. Here, to improve the predictive power of ex vivo disease modelling we propose using hiPSC technology to focus on representatives of patient subgroups stratified for genomic and/or phenomic features and neurobiological cell systems. Therefore, this review will outline the evidence for the involvement of OPCs/OLs in SCZ in the context of their proposed functions, including myelination and axon support, the implications for hiPSC-based cellular disease modelling and potential strategies for patient selection.

Oligodendrocytes as A New Therapeutic Target in Schizophrenia: From Histopathological Findings to Neuron-Oligodendrocyte Interaction

“…Until recently, most insights into SZ have been generated from postmortem tissue samples and imaging, genetic, pharmacological, and animal studies. Cellular reprogramming methods to generate induced pluripotent stem cells (iPSC) now provide a new opportunity to model the complex polygenetic conditions of SZ by generating patient-derived human iPSC (hiPSC)-based neurobiological test systems [92,93]. The pioneer work of Brennand et al (2011) first characterized hiPSC-derived neurons from SZ patients and revealed decreased neuronal connectivity, decreased neurites, and decreased levels of post-synaptic protein PSD95 [94].…”

“…An additional advantage is the reduced cellular heterogeneity. Probably the most important disadvantages of directed differentiation approaches are their limitations in studying the early developmental aspects of SZ [93]. Oligodendrocyte progenitor cells and oligodendrocytes are heterogeneous across brain regions and vary with age [107], so investigations are needed that address this diversity.…”

“…Despite the tremendous progress in twoand three-dimensional hiPSC-derived myelinating neurobiological test systems, these systems are always limited by their construct validity in brain disorders, where circuit levels contribute to behavioral and cognitive deficits. Nevertheless, patient-specific cellular systems enable the study of disease-associated endophenotypes, such as axonal support or multiple aspects of myelination, and expand the experimental repertoire in psychiatric research [93]. Transcriptomic studies…”

Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies

“…Moreover, an oligodendrocyte deficit can cause impaired myelination with a subsequent lack of nerve impulse transmission and cognitive impairment related to SCZ. It has also been hypothesized that inflammation in the brain along with microglia overactivity is involved in oligodendrocyte dysfunction (Raabe et al 2018(Raabe et al , 2019.…”

“…(1) cells from tissues other than the brain may sometimes be contaminated, (2) due to different embryonal origins, microglia cannot be included in almost all of the iPSC cellderived brain models and (3) conditions arising from longlasting processes such as aging and maturation are difficult to reproduce when using brain organoids (Quadrato et al 2016;Raabe et al 2018Raabe et al , 2019.…”