iPSC toolbox for understanding and repairing disrupted brain circuits in autism

Abstract

Over the past decade, tremendous progress has been made in defining autism spectrum disorder (ASD) as a disorder of brain connectivity. Indeed, whole-brain imaging studies revealed altered connectivity in the brains of individuals with ASD, and genetic studies identified rare ASD-associated mutations in genes that regulate synaptic development and function. However, it remains unclear how specific mutations alter the development of neuronal connections in different brain regions and whether altered connections can be restored therapeutically. The main challenge is the lack of preclinical models that recapitulate important aspects of human development for studying connectivity. Through recent technological innovations, it is now possible to generate patient- or mutation-specific human neurons or organoids from induced pluripotent stem cells (iPSCs) and to study altered connectivity in vitro or in vivo upon xenotransplantation into an intact rodent brain. Here, we discuss how deficits in neurodevelopmental processes may lead to abnormal brain connectivity and how iPSC-based models can be used to identify abnormal connections and to gain insights into underlying cellular and molecular mechanisms to develop novel therapeutics.

MARK2variants cause autism spectrum disorderviathe downregulation of WNT/β-catenin signaling pathway

“…Multiple neurodevelopmental processes, including proliferation/neurogenesis, migration, neurite outgrowth, morphogenesis of dendrites and dendritic spines, and synaptogenesis and gliogenesis, have been reported to be involved in ASD. [45][46][47][48] .…”

“…Multiple neurodevelopmental processes, including proliferation/neurogenesis, migration, neurite outgrowth, morphogenesis of dendrites and dendritic spines, and synaptogenesis and gliogenesis, have been reported to be involved in ASD. 45–48 . Although the pathophysiological mechanism by which MARK2 loss underlies ASD in humans is unknown, the role of MARK2 in neuronal development is recognized, 11–16 including mediation of neurite outgrowth, 11, 12, 15 establishment of neuronal polarity, 11, 12, 15 specification of neuronal dendrites/axons, 11, 12, 16 and promotion of neuronal migration.…”

Bridging the translational gap: what can synaptopathies tell us about autism?

“…Modelling neuronal circuitry is highly complex and is a primary challenge in the translation of outcomes from of hiPSC-neuron studies to animal models of synaptopathies. Two dimensional (2D) iPSCneuron culture can reveal the molecular basis of neuronal circuitry but cannot feasibly replicate it's intricacies (Chiola et al, 2022). Three dimensional (3D) iPSC-models, such as organoids and assembloids, more closely represent in vivo circuitry but they lack the coordination and organisation necessary to mimic accurate circuitry-level communication without cortical implantation (Revah et al, 2022).…”

Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids

“…hBOs generated from patient-derived hiPSCs have been used to understand the cellular mechanisms underlying the cortical malformations observed in Miller-Dieker and Pretzel syndromes (Bershteyn et al, 2017 ; Iefremova et al, 2017 ; Dang et al, 2021 ). iPSC-derived hBOs have also been used to identify changes in neuronal composition and molecular alterations associated with Rett syndrome (Gomes et al, 2020 ; Samarasinghe et al, 2021 ), idiopathic ASD (Mariani et al, 2015 ; Chiola et al, 2021 ), microcephaly (Lancaster et al, 2013 ), schizophrenia (Stachowiak et al, 2017 ; Khan et al, 2020 ), and other disorders. However, patient-to-patient genetic variability can be a challenge for directly linking cellular phenotypic outcomes to a specific genetic cause.…”