Dysregulation of neuron differentiation in an autistic savant with exceptional memory

Jinjing Song,Xu Zhang,Xiujuan Yang,Ying Zhou,Guang He,Weibo Niu,Nengpeng Zhan,Zhuxi Liu,Xuelian Fan,Lulu Song,Abdul Aziz Khan,Yifang Kuang,Weidong Li,Lei Chen

doi:10.1186/s13041-019-0507-7

Jinjing Song, Xu Zhang + Show 12 more

Open Access

https://doi.org/10.1186/s13041-019-0507-7

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Abstract

Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders without a unique or definite underlying pathogenesis. Although savant syndrome is common in ASD, few models are available for studying the molecular and cellular mechanisms of this syndrome. In this study, we generated urinary induced pluripotent stem cells (UiPSCs) from a 13-year-old male autistic savant with exceptional memory. The UiPSC-derived neurons of the autistic savant exhibited upregulated expression levels of ASD genes/learning difficulty-related genes, namely PAX6, TBR1 and FOXP2, accompanied by hypertrophic neural somas, enlarged spines, reduced spine density, and an increased frequency of spontaneous excitatory postsynaptic currents. Although this study involved only a single patient and a single control because of the rarity of such cases, it provides the first autistic savant UiPSC model that elucidates the potential cellular mechanisms underlying the condition.

Highlights

Autism spectrum disorder (ASD) is a constellation of early-onset neurodevelopmental disorders
We discovered that compared with control neurons, upregulated transcription of ASD risk genes co-occurred with dysregulated cellular cortical development and synaptogenesis in the urinary induced pluripotent stem cells (UiPSCs)-derived neurons of the autistic savant on day 42 after neural progenitor cells (NPCs) differentiation
Generation of UiPSC-derived neurons of the autistic savant Exfoliated renal epithelial cells were isolated from the urine of the autistic savant and an unrelated healthy control; the cells were cultured for expansion (Fig. 1a and b and Additional file 3: Figure S1a)

Summary

Introduction

Autism spectrum disorder (ASD) is a constellation of early-onset neurodevelopmental disorders It is characterized by social communication deficits and repetitive sensory-motor behaviors, and it is often accompanied by abnormalities in language development [1]. A group of 65 genes were identified with strongest statistical evidence, and this identification has expanded knowledge of the sets of highest-confidence risk genes associated with ASD [9]. Among these genes, TBR1—a putative transcription factor (TF)—is highly expressed in glutamatergic early-born cortical neurons; it dictates the expression of other risk genes, controls cortical development, and is implicated in intellectual disability [10,11,12]. Following TBR1 dictation, FOXP2 is related to some severe speech-language disorders and plays a role in cortical neurogenesis [18,19,20,21]

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