Human stem cell-based models for studying autism spectrum disorder-related neuronal dysfunction

Abstract

The controlled differentiation of pluripotent stem cells (PSCs) into neurons and glia offers a unique opportunity to study early stages of human central nervous system development under controlled conditions in vitro. With the advent of cell reprogramming and the possibility to generate induced pluripotent stem cells (iPSCs) from any individual in a scalable manner, these studies can be extended to a disease- and patient-specific level. Autism spectrum disorder (ASD) is considered a neurodevelopmental disorder, with substantial evidence pointing to early alterations in neurogenesis and network formation as key pathogenic drivers. For that reason, ASD represents an ideal candidate for stem cell-based disease modeling. Here, we provide a concise review on recent advances in the field of human iPSC-based modeling of syndromic and non-syndromic forms of ASD, with a particular focus on studies addressing neuronal dysfunction and altered connectivity. We further discuss recent efforts to translate stem cell-based disease modeling to 3D via brain organoid and cell transplantation approaches, which enable the investigation of disease mechanisms in a tissue-like context. Finally, we describe advanced tools facilitating the assessment of altered neuronal function, comment on the relevance of iPSC-based models for the assessment of pharmaceutical therapies and outline potential future routes in stem cell-based ASD research.

Keywords: Autism spectrum disorder; Brain organoids; Cell reprogramming; In vitro differentiation; Induced pluripotent stem cells; Neuronal connectivity.

Fig. 1

Cellular systems and functional read-outs used for stem cell-based modeling of ASD. Patient-specific and control iPSC lines are generated by classic reprogramming. Genome editing enables the repair of disease-related genetic variants or targeted insertion of ASD-related mutations into a control background, thereby providing isogenic pairs of disease-specific and control iPSC lines. Extrinsic factor-based differentiation is used to generate mixed neuronal cultures, which can be enriched for excitatory or inhibitory neurons depending on the culture conditions. More precise lineage specification can be achieved by transcription factor-based forward programming into induced glutamatergic or GABAergic neurons (iGlutNs or iGABANs; see also Table 1). 3D models such as cerebral organoids or xenotransplantation of human cells into the rodent brain might be used to study pathophenotypes in a tissue-like context. So far, ASD-related functional alterations have mainly been studied using patch clamping (PC), multi-electrode arrays (MEAs) and functional imaging (FI). Components of the figure were adapted from Servier Medical Art (https://smart.servier.com/#). CTRL: control; *Mixed neuronal cultures might be enriched for e.g. glutamatergic neurons

Box 1

Next generation tools for assessing neuronal connectivity and function in vivo