Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS

Ross, P. Joel; Zhang, Wen Bo; Mok, Rebecca S.F.; Zaslavsky, Kirill; Deneault, Éric; D’Abate, Lia; Rodrigues, Deivid C.; Yuen, Ryan K. C.; Faheem, Muhammad; Mufteev, Marat; Piekna, Alina; Wei, Wei; Pasceri, Peter; Landa, Rebecca; Nagy, András; Varga, Balázs; Salter, Michael W.; Scherer, Stephen W.; Ellis, James

doi:10.1016/j.biopsych.2019.07.014

Cited by 63 publications

(64 citation statements)

References 61 publications

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“…Additionally, in contrast to the findings with SHANK3, SHANK2 loss of function mutations led to an increase in the number of synapses, as well as in the complexity of the dendritic tree [146]. Individuals with NLGN4 [138] and one individual with a PTCHD1-AS mutation [140] also showed an increase in the number of synapses.…”

Section: Neuronal Differentiation and Morphologycontrasting

confidence: 63%

“…Conversely, genetically defined forms of ASD, mutation in NRXN1, and 22q11.2 deletion showed evidence of a decreased proliferation rate [124,135,144]. However, it is important to note that not all studies that examined cell cycle found changes in ASD [116,125,140,143]. The acceleration in cell cycle in idiopathic ASD supports a finding from toddlers with ASD in which cell cycle gene networks were positively correlated with brain volume [155].…”

Section: Cell Cycle and Proliferationmentioning

confidence: 74%

“…One study also showed a reduction in spine density [129], though this result was not replicated by a different group [127]. Similar decreases in dendritic tree complexity were also found in neurons derived from individuals with Angelman syndrome [122] and in one individual with a PTCHD1-AS mutation [140]. However, not all genetic forms of ASD followed this pattern of decreased complexity of the dendritic tree.…”

Section: Neuronal Differentiation and Morphologymentioning

confidence: 88%

“…Two kinds of genetic modeling have been performed using cells either from individuals whose genetic contributions are unknown or undefined, so called idiopathic [59,60,[112][113][114][115][116][117][118][119][120], or from individuals harboring major effect mutations that are presumed causal or which have been engineered to carry these mutations. These mutations include ASD-associated CNVs such as 15q11q13 deletion (Angelman syndrome) [121] and duplication (Dup15q syndrome) [122], 22q11.2 deletion (DiGeorge syndrome) [123,124], 16p11.2 deletion and duplication [125], and 15q13.3 deletion [126], as well as single-gene mutations including SHANK3 [127][128][129][130], CHD8 [131,132], NRXN1 [133][134][135][136][137], NLGN4 [138], EHMT1 (Kleefstra syndrome) [139], PTCHD1-AS [140], UBE3A (Angelman's syndrome) [141], and CACNA1C (Timothy syndrome) [142] (summarized in Table 1). In this review, we will not discuss fragile X syndrome, Rett's syndrome, and tuberous sclerosis-related autism as they have all been extensively reviewed previously [148][149][150][151][152][153][154].…”

Section: Main Findings From Stem Cell Models Of Asd To Datementioning

confidence: 99%

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Human in vitro models for understanding mechanisms of autism spectrum disorder

Gordon

Geschwind

2020

Molecular Autism

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Early brain development is a critical epoch for the development of autism spectrum disorder (ASD). In vivo animal models have, until recently, been the principal tool used to study early brain development and the changes occurring in neurodevelopmental disorders such as ASD. In vitro models of brain development represent a significant advance in the field. Here, we review the main methods available to study human brain development in vitro and the applications of these models for studying ASD and other psychiatric disorders. We discuss the main findings from stem cell models to date focusing on cell cycle and proliferation, cell death, cell differentiation and maturation, and neuronal signaling and synaptic stimuli. To be able to generalize the results from these studies, we propose a framework of experimental design and power considerations for using in vitro models to study ASD. These include both technical issues such as reproducibility and power analysis and conceptual issues such as the brain region and cell types being modeled.Early development as a critical period for ASD susceptibility

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Section: Neuronal Differentiation and Morphologycontrasting

confidence: 63%

Section: Cell Cycle and Proliferationmentioning

confidence: 74%

Section: Neuronal Differentiation and Morphologymentioning

confidence: 88%

Section: Main Findings From Stem Cell Models Of Asd To Datementioning

confidence: 99%

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Human in vitro models for understanding mechanisms of autism spectrum disorder

Gordon

Geschwind

2020

Molecular Autism

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“…Alterations in GABAergic neurotransmission are implicated in ASD affectation and may result from disruptions of synaptic development, resulting in imbalanced excitatory and inhibitory neuronal activity (39,48). Since most in vitro modeling studies characterize neurodevelopmental phenotypes only in excitatory neurons (10,19,49,50), the extent to which GABAergic inhibitory neurodevelopment is affected in iPSC models of ASD remains largely unexplored. This work suggests that assessing phenotypes in both excitatory and inhibitory neurons may be beneficial for identifying such neuronal cell type-specific alterations of neurodevelopment that may contribute to ASD.…”

Section: Discussionmentioning

confidence: 99%

Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involvingCHRNA7

Meganathan¹,

Prakasam²,

Baldridge³

et al. 2020

Preprint

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Background: Copy number variants at chromosome 15q13.3 contribute to liability for multiple intellectual and developmental disabilities (IDDs) including Autism Spectrum Disorder (ASD). Individuals with duplications of this interval, which includes the gene CHRNA7, have IDDs with variable penetrance. However, the basis of such differential affectation remains uncharacterized. Methods:Induced pluripotent stem cell (iPSC) models were generated from two first degree relatives with the same 15q13.3 duplication, a boy with distinct features of autism and emotional dysregulation (the affected proband, AP) and his clinically unaffected mother (the UM). These models were compared to unrelated control subjects lacking this duplication (UC, male and female). iPSC-derived neural progenitors and cortical neuroids consisting of cortical excitatory and inhibitory neurons were used to model potential contributors to neuropsychiatric impairment. Results:The AP-derived model uniquely exhibited disruptions of cellular physiology and neurodevelopment not observed in either the UM or in unrelated male and female controls. These included enhanced neural progenitor proliferation but impaired neuronal differentiation, maturation, and migration, and increased endoplasmic reticulum (ER) stress in neural progenitors. Both the AP model's neuronal migration deficit and elevated ER stress could be selectively rescued by different pharmacologic agents. Neuronal gene expression was also specifically dysregulated in the AP, including altered expression of genes related to behavior, psychological disorders, neuritogenesis, neuronal migration, and WNT signaling. By contrast with these AP-specific phenotypes, both the AP-and UM-derived neurons exhibited shared alterations of neuronal function, including elevated cholinergic activity consistent with increased homomeric CHRNA7 channel activity. Conclusion:Together, these data define both affectation-specific phenotypes seen only in the AP, as well as abnormalities observed in both individuals with CHRNA7 duplication, the AP and UM, but not in UC-derived neurons. This is, to our knowledge, the first study to use a human stem cell-based platform to study the basis of variable affectation in cases of 15q13.3 duplication at the cellular, molecular, and functional levels. This work suggests potential approaches for suppressing abnormal neurodevelopment or physiology that may contribute to severity of affectation in this proband. Some of these AP-specific neurodevelopmental anomalies, or the functional anomalies observed in both 15q13.3 duplication carriers (the AP and UM), could also contribute to the variable phenotypic penetrance seen in other individuals with 15q13.3 duplication. Ethics approval and consent to participateSubjects were consented for biobanking and iPSC line generation by the Washington University Institutional

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The potential of induced pluripotent stem cells for discriminating neurodevelopmental disorders

Stock

Jeckel

Kraushaar

et al. 2020

Stem Cells Translational Medicine

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Studying human disease-specific processes and mechanisms in vitro is limited by a lack of valid human test systems. Induced pluripotent stem cells (iPSCs) evolve as an important and promising tool to better understand the molecular pathology of neurodevelopmental disorders. Patient-derived iPSCs enable analysis of unique disease mechanisms and may also serve for preclinical drug development. Here, we review the current knowledge on iPSC models for schizophrenia and autism spectrum disorders with emphasis on the discrimination between them. It appears that transcriptomic analyses and functional read-outs are the most promising approaches to uncover specific disease mechanisms in vitro.

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Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS

Cited by 63 publications

References 61 publications

Human in vitro models for understanding mechanisms of autism spectrum disorder

Human in vitro models for understanding mechanisms of autism spectrum disorder

Alterations in neuronal physiology, development, and function associated with a common duplication of chromosome 15 involvingCHRNA7

The potential of induced pluripotent stem cells for discriminating neurodevelopmental disorders

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