Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD

Culotta and Penzes Molecular Autism (2020) 11:32 https://doi.org/10.1186/s13229-020-00339-0 REVIEW Open Access Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD Lorenza Culotta1,3 and Peter Penzes1,2,3* Abstract Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and repetitive or restricted behaviors. ASD subjects exhibit complex genetic and clinical heterogeneity, thus hindering the discovery of pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity, one hypothesis that has emerged is that ASD arises from a disruption of the neuronal network activity due to perturbation of the synaptic excitation and inhibition (E/I) balance. The development of induced pluripotent stem cell (iPSC) technology and recent advances in neuronal differentiation techniques provide a unique opportunity to model complex neuronal connectivity and to test the E/I hypothesis of ASD in human-based models. Here, we aim to review the latest advances in studying the different cellular and molecular mechanisms contributing to E/I balance using iPSC-based in vitro models of ASD. Keywords: Autism spectrum disorder, Induced pluripotent stem cell, Excitation/inhibition balance Background Autism spectrum disorder (ASD) represents a spectrum of early-onset neurodevelopmental disorders characterized by persistent deficits in social interaction and communication, as well as repetitive patterns of behavior and restricted interests or activities (Diagnostic and Statistical Manual of Mental Disorders [DSM-5]). Current population prevalence of ASD is estimated at ∼ 1.5% in developed countries around the world and, to date, there are no effective cures [1, 2]. ASD patients display considerable phenotypic heterogeneity and they often present comorbid neurological and mental conditions, such as epilepsy, intellectual disability (ID), obsessivecompulsive disorder (OCD), and attention-deficit hyperactivity disorder (ADHD) [3]. * Correspondence: 1 Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 2 Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Full list of author information is available at the end of the article ASD can be classified into syndromic and nonsyndromic forms [4–7]. Syndromic ASD accounts for a small percentage of total ASD cases; it typically occurs with a clinical presentation in association with secondary phenotypes and/or dysmorphic features [6]. Most of the syndromic forms of ASD have a known genetic cause, often involving chromosomal abnormalities or mutations in a single gene. On the other hand, non-syndromic ASD accounts for the vast majority of ASD cases and occurs without additional symptoms. In contrast to the syndromic ASD, most of the non-syndromic forms of ASD have unknown genetic etiology [5]. Even though the genetics underlying ASD is complex, ASD is primarily considered a genetic disorder, with family and twins studies suggesting the heritability of ASD to be higher than 80% [8–12]. Genetic studies have identified several autism-susceptibility (or risk) genes (e.g., SHANK- and NRXN-family genes) and copy number variation (CNV) loci (e.g., 16p11.2 deletion and 15q11-q13 duplication), facilitating the molecular diagnosis of ASD cases. Many © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Culotta and Penzes Molecular Autism (2020) 11:32 of the identified ASD risk genes are key regulators of synaptic plasticity, with their gene products involved in modulating synaptic strength or density, cell adhesion, chromatin remodeling, transcription, cytoskeleton dynamics and, ultimately, neuronal connectivity [13–15]. In addition to genetic risk factors, several studies suggest that environmental factors may contribute to ASD risk, supporting the hypothesis that ASD could result from the effects of diverse biological and/or psychological factors, like genetic factors, environmental factors, and the interplay between genetic background and environmental factors [16–18]. The environmental factors could be prenatal, perinatal, and postnatal, and some examples include in utero exposure to medications, such as thalidomide and valproate [19, 20], parental age of birth, and gestational complications such as diabetes and bleeding [11, 21]. The speculated existence of interactions between genetic factors and environmental factors suggests that individuals with ASD may react differently to the same environmental stimulus: indeed, studies of animal models have shown that environmental factor, such as hypoxia, oxidative stress, and maternal immune activation, may increase autism risk by interacting with genetic defects in synaptic function [22–24]. One of the proposed etiological mechanisms of ASD is the disruption of the balance between excitation and inhibition (E/I balance) in key cortical and subcortical neuronal circuits [25–30]. E/I balance is a crucial player in the normal development and function of the brain, and different homeostatic and developmental processes appear to be involved in maintaining E/I balance at the level of single cells and large-scale neuronal circuits [26]. At the single neuron level, the balance between excitatory and inhibitory synaptic inputs is critical for information processing, and therefore is highly regulated and structurally organized to allow spatially precise E/I balance across dendritic segments [31, 32]. At the network level, E/I balance is usually considered as a stable global level of activity within a particular circuit, being the balance of excitation and inhibition important for optimal tuning of the circuits to respond to salient inputs [33, 34]. To da (...truncated)