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Transition from Animal-Based to Human Induced Pluripotent Stem Cells (iPSCs)-Based Models of Neurodevelopmental Disorders: Opportunities and Challenges

CELLS (2023)

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Article Cell & Tissue Engineering

Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors

Hiruy S. Meharena et al.

Summary: The study reveals that iPSC-derived NPCs with T21 exhibit genome-wide chromosomal introversion, disruption of lamina-associated domains, and global chromatin accessibility changes, resembling characteristics of senescent cells. Treatment of T21-harboring NPCs with senolytic drugs alleviates the dysfunctions associated with DS, providing a link between T21 and global transcriptional disruption.

CELL STEM CELL (2022)

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Article Developmental Biology

Early Appearance of Dendritic Alterations in Neocortical Pyramidal Neurons of the Ts65Dn Model of Down Syndrome

Beatrice Uguagliati et al.

Summary: This study demonstrates the presence of dendritic alterations in neonatal Ts65Dn mice, mainly involving the basal and apical domains. These findings are important for understanding the mechanisms underlying dendritic alterations in DS and for developing therapeutic interventions.

DEVELOPMENTAL NEUROSCIENCE (2022)

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Article Neurosciences

DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors

Peng Chen et al.

Summary: Mutations in cell adhesion molecules (CAMs) can lead to abnormal synapse formation and maturation, possibly contributing to autism spectrum disorders (ASDs). This study discovered that the DSCAM gene, a high-risk gene for autism, plays a role in preventing premature spine maturation and excessive glutamatergic transmission. Deficiency of DSCAM led to accelerated dendritic spine maturation and autism-like behaviors in mice.

JOURNAL OF NEUROSCIENCE (2022)

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Review Neurosciences

Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids

Bipan K. Deb et al.

Summary: Neurodevelopmental disorders (NDDs) are a group of diseases with early life onset that are characterized by developmental delay, cognitive deficits, and behavioral conditions. Recent evidence suggests that brain somatic mutations may contribute to NDDs, and human brain organoids provide a powerful model for studying these mutations.

FRONTIERS IN MOLECULAR NEUROSCIENCE (2022)

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Article Education, Special

Latent profiles of autism symptoms in children and adolescents with Down syndrome

D. J. Fidler et al.

Summary: This study examined ASD symptom profiles in individuals with Down syndrome (DS) and identified three different profiles, which can inform more personalized support and therapeutic approaches for this population.

JOURNAL OF INTELLECTUAL DISABILITY RESEARCH (2022)

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Article Biochemistry & Molecular Biology

Abnormal mitochondria in Down syndrome iPSC-derived GABAergic interneurons and organoids

Lei Xu et al.

Summary: Down syndrome is associated with developmental brain disorders and neurological dysfunction caused by trisomy 21. In this study, abnormal mitochondrial clustering and impaired mitochondrial function were observed in GABAergic interneurons and MGE organoids from DS patients. The DSCAM-PAK1 pathway was identified as a potential target for correcting mitochondrial dysfunction in DS cells.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE (2022)

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Article Medicine, Research & Experimental

Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome

Jeffrey L. Neul et al.

Summary: A drug trial using trofinetide in females with Rett syndrome (RTT) showed significant improvement compared to placebo on multiple measures. A Phase 3 trial will further evaluate the efficacy and safety of trofinetide using disease-specific and novel scales to assess core symptoms of RTT, quality of life, and caregiver burden.

CONTEMPORARY CLINICAL TRIALS (2022)

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Article Biochemistry & Molecular Biology

APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer's pathology in trisomy 21 neurons

Chun- Wu et al.

Summary: This study used hiPSCs and CRISPR-Cas9 gene editing to investigate the role of chromosome 21 candidate genes in AD-related neuronal phenotypes. The findings suggest that normalization of copy number of APP and DYRK1A can rescue elevated tau phosphorylation in T21 neurons, while reductions of RCAN1 and SYNJ1 do not have this effect. The study also identified disruptions in the axonal cytoskeletal network and presynaptic proteins in T21 neurons, which play critical roles in axonal transport and synaptic vesicle cycling. These findings provide insights into the molecular mechanisms underlying synaptic loss and axonal degeneration in Down syndrome and early-onset AD.

MOLECULAR PSYCHIATRY (2022)

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Review Genetics & Heredity

Electrophysiological and Behavioral Evidence for Hyper- and Hyposensitivity in Rare Genetic Syndromes Associated with Autism

Anastasia Neklyudova et al.

Summary: Our study reviewed brain activity abnormalities in genetic syndromes associated with autistic symptoms. We tentatively categorized the syndromes into hyper-sensitive and hypo-sensitive, suggesting a segregation of individuals with idiopathic autism spectrum disorder (ASD) who exhibit both hyper-sensitivity and hypo-sensitivity. These divisions are linked to abnormalities in different genes that are causative to the syndromes and associated with synaptic transmission, cell growth, sensory sensitivity, and translational and transcriptional regulation. The relationship between excitation/inhibition imbalance related to GABAergic signaling and the interplay of tonic and phasic inhibition in different brain regions may underlie these divisions, although further research is needed. Multi-site collaboration and a common research protocol are recommended for future investigations, especially considering the rarity of genetic syndromes, which should include an exploration of all modalities and stages of sensory processing as well as potential biomarkers of GABAergic signaling.

GENES (2022)

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Article Cell & Tissue Engineering

Altered patterning of trisomy 21 interneuron progenitors

Yathindar Giffin-Rao et al.

Summary: Individuals with Down syndrome (DS) have smaller brains with fewer neurons, indicating impaired neurogenesis during development. This study found a reduction of calretinin-expressing interneurons in the DS cortex and demonstrated that altered WNT signaling contributes to the defective development of cortical interneurons in DS.

STEM CELL REPORTS (2022)

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Article Biochemistry & Molecular Biology

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants

Sara Perego et al.

Summary: This study investigated the MECP2 gene variants associated with different pathological phenotypes in Rett syndrome. iPSC-neurons were generated from the blood of Rett syndrome patients and compared with control neurons. Morphological and electrophysiological analyses revealed specific cellular phenotypes correlated with different MECP2 mutations. The findings suggest that these cellular markers could be used for drug testing and translational research.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Article Cell Biology

Migration deficits of the neural crest caused by CXADR triplication in a human Down syndrome stem cell model

Huanyao Liu et al.

Summary: This study explores the potential underlying causes of craniofacial dysmorphology in individuals with Down syndrome (DS) and identifies potential therapeutic targets. The researchers find that migration defects in neural crest cells may contribute to craniofacial anomalies in DS, and they discover that the triplication of the CXADR gene in DS cells is partially responsible for these migration defects.

CELL DEATH & DISEASE (2022)

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Article Biochemistry & Molecular Biology

DNA Methylation Profiles of GAD1 in Human Cerebral Organoids of Autism Indicate Disrupted Epigenetic Regulation during Early Development

Georgina Pearson et al.

Summary: DNA methylation analysis has shown promise in identifying biomarkers for neuropsychiatric disorders, and our study found differential methylation patterns in the GAD1 gene of individuals with autism spectrum disorder.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Review Cell Biology

Brain organoids: Establishment and application

Hao Chen et al.

Summary: Brain organoids, generated through the differentiation of pluripotent stem cells, provide a valuable platform for studying human brain development, disease modeling, and drug screening.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2022)

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Article Neurosciences

Neurogenesis and neuronal differentiation in the postnatal frontal cortex in Down syndrome

Emma C. Utagawa et al.

Summary: The study revealed the impact of trisomy 21 on postnatal cortical development, including alterations in neuronal migration, neurogenesis, and cellular lamination, which may contribute to cognitive impairment.

ACTA NEUROPATHOLOGICA COMMUNICATIONS (2022)

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Article Biochemistry & Molecular Biology

Shank2/3 double knockout-based screening of cortical subregions links the retrosplenial area to the loss of social memory in autism spectrum disorders

Debora Garrido et al.

Summary: Members of the Shank protein family are linked to autism spectrum disorders (ASDs). Researchers created a double knockout mouse model for Shank2 and Shank3 genes, which exhibited severe symptoms of autism and other comorbidities. By deleting Shank2 and Shank3, researchers identified the involvement of the retrosplenial area in social memory impairment, a core symptom of ASD. Neuronal activation could rescue the social impairment caused by Shank2/3 depletion.

MOLECULAR PSYCHIATRY (2022)

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Article Multidisciplinary Sciences

Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming

Hyosang Kim et al.

Summary: Early postnatal serotonin modulation can prevent adult stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming.

NATURE COMMUNICATIONS (2022)

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Article Behavioral Sciences

Early life stress exacerbates behavioural and neuronal alterations in adolescent male mice lacking methyl-CpG binding protein 2 (Mecp2)

Jose Vicente Torres-Perez et al.

Summary: This study finds that maternal separation exacerbates phenotypical alterations associated with lack of MeCP2 in adolescent males.

FRONTIERS IN BEHAVIORAL NEUROSCIENCE (2022)

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Article Psychiatry

Wide spectrum of neuronal and network phenotypes in human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations

Rebecca S. F. Mok et al.

Summary: Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the MECP2 gene. This study shows that different mutations in MECP2 can lead to a wide range of phenotypes in terms of neuron morphology, electrophysiology, and circuitry.

TRANSLATIONAL PSYCHIATRY (2022)

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Review Pharmacology & Pharmacy

Reversibility and therapeutic development for neurodevelopmental disorders, insights from genetic animal models

Platon Megagiannis et al.

Summary: This article reviews the progress in the diagnosis, etiology discovery, modeling, and mechanistic understanding of neurodevelopmental disorders (NDDs) from both fundamental and clinical research. It introduces breakthroughs in the reversal studies of NDDs using genetically engineered models and discusses the application and challenges of cutting-edge technologies in NDDs therapeutic development.

ADVANCED DRUG DELIVERY REVIEWS (2022)

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Article Multidisciplinary Sciences

Passage number affects differentiation of sensory neurons from human induced pluripotent stem cells

Erica L. Cantor et al.

Summary: Lower passage numbers of iPSCs are better suited for differentiation into peripheral sensory neurons, as they more accurately recapitulate the phenotype. This finding is significant for neurological disease modeling and drug discovery.

SCIENTIFIC REPORTS (2022)

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Article Biochemistry & Molecular Biology

miR-92a-2-5p Regulates the Proliferation and Differentiation of ASD-Derived Neural Progenitor Cells

Wenting Zhuang et al.

Summary: This study reveals the negative regulatory effect of miR-92a-2-5p on the proliferation and neuronal differentiation of ASD neural progenitor cells (NPCs). It also identifies the interaction between miR-92a-2-5p and the genetic risk factor DLG3 for ASD, suggesting the potential importance of miR-92a-2-5p in neuropsychiatric disorders.

CURRENT ISSUES IN MOLECULAR BIOLOGY (2022)

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Article Biochemistry & Molecular Biology

Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder

K. Griesi-Oliveira et al.

Summary: Evaluation of expression profile in ASD patients using iPSC-derived neuronal models revealed dysregulated gene modules related to protein synthesis, synapse/neurotransmission, and translation. The comparison of findings showed that the synapse-related module is consistently upregulated in iPSC-derived neurons-more similar to fetal brain, while downregulated in postmortem brain tissue, indicating a reliable association to ASD and suggesting developmental dysregulation in ASD individuals. This network's expression pattern could potentially serve as a biomarker for ASD and a therapeutic target.

MOLECULAR PSYCHIATRY (2021)

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Review Cell Biology

Deconstructing and reconstructing the human brain with regionally specified brain organoids

Yangfei Xiang et al.

Summary: Brain organoids, three-dimensional neural cultures that mimic the spatiotemporal organization and function of the brain, are valuable tools for studying human brain development and diseases. Various region-specific human brain organoids have been developed to model distinct parts of the brain, offering unique opportunities for exploring regional interactions and advancing brain research. However, challenges exist in driving forward the technology and applications of brain organoids for future studies.

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY (2021)

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Article Biology

Human Trisomic iPSCs from Down Syndrome Fibroblasts Manifest Mitochondrial Alterations Early during Neuronal Differentiation

Nunzia Mollo et al.

Summary: Down syndrome, caused by an extra copy of chromosome 21, is associated with mental retardation and defects in neuronal development potentially due to mitochondrial dysfunction. Stem cells derived from individuals with Down syndrome showed a propensity towards developing as glial cells and exhibited early mitochondrial defects. This model can be used to further study the impact of mitochondrial dysfunction on neuronal development.

BIOLOGY-BASEL (2021)

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Article Cell Biology

Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2

Xiaoying Chen et al.

Summary: Rett syndrome is a progressive neurodevelopmental disorder caused by MeCP2 mutations, resulting in stable neuronal maturation deficits. Knockdown of MeCP2 leads to more severe neuronal impairments compared to RTT iPSC-derived neurons, which show partial preservation of function. The study also reveals graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, providing important insights for future therapeutic development.

PROTEIN & CELL (2021)

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Article Biology

JNK signaling provides a novel therapeutic target for Rett syndrome

Clara Alice Musi et al.

Summary: The study revealed altered JNK signaling in models of RTT and suggested that treatment with a specific JNK inhibitor can prevent clinical symptoms, showing consistent results at the cellular, molecular, and functional levels. This provides the first evidence that JNK plays a crucial role in RTT and its inhibition could be a new potential therapeutic tool for tackling this disorder.

BMC BIOLOGY (2021)

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Review Cell Biology

Modeling neurodevelopment in a dish with pluripotent stem cells

Kent Imaizumi et al.

Summary: Pluripotent stem cells have the ability to differentiate into all cell types in the body, mirroring the developmental processes of embryogenesis. Neural induction and modeling of PSCs offer insights into neurodevelopment, particularly in studying human-specific neurodevelopment and the mechanisms of human brain evolution. Challenges and future directions in advancing PSC-based neural modeling are also discussed.

DEVELOPMENT GROWTH & DIFFERENTIATION (2021)

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Article Medicine, Research & Experimental

Pharmacological reversal of synaptic and network pathology in human MECP2-KO neurons and cortical organoids

Cleber A. Trujillo et al.

Summary: Variations in the X-linked MECP2 gene can cause Rett syndrome, and human pluripotent stem cell technology provides a platform for studying neuropathology and testing potential treatments. Through advanced stem cell technologies, research has identified two compounds that can reverse neuropathologic phenotypes and networks in human models.

EMBO MOLECULAR MEDICINE (2021)

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Article Neurosciences

Conditional Pten knockout in parvalbumin- or somatostatin-positive neurons sufficiently leads to autism-related behavioral phenotypes

Sangyep Shin et al.

Summary: The disrupted GABAergic neurons in individuals with autism spectrum disorder (ASD) and animal models for ASD have been extensively described but their contribution to autism-related behavioral phenotypes is not well understood. This study demonstrated that mice with conditional Pten knockout in parvalbumin (PV)-expressing or somatostatin (Sst)-expressing neurons exhibited ASD-related behaviors, including social deficits, repetitive behaviors, impaired motor coordination/learning, hyperlocomotion, and anxiety-like behaviors. It provides evidence that both PV- and Sst-neurons may play a critical role in ASD symptoms.

MOLECULAR BRAIN (2021)

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Article Biochemistry & Molecular Biology

Down syndrome is an oxidative phosphorylation disorder

M. Pilar Bayona-Bafaluy et al.

Summary: Down syndrome is the most common genomic disorder of intellectual disability caused by trisomy of chromosome 21. Genes in this chromosome repress mitochondrial biogenesis, leading to a defect in oxidative phosphorylation as an early and general event in individuals with Down syndrome. Drugs that enhance mitochondrial biogenesis have been tested in mouse models, showing potential in restoring neurogenesis and cognitive defects associated with Down syndrome.

REDOX BIOLOGY (2021)

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Article Clinical Neurology

Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly

Charline Jansch et al.

Summary: This study presents an efficient method for generating functionally active neurons with 5-HT specification from hiPSCs, characterized by high-end fluorescence imaging and electrophysiological techniques. The differentiated cells synthesize 5-HT, express specific markers, and exhibit electrophysiological signatures of serotonergic neurons, including the formation of synapses. These hiPSC-derived 5-HT specific neuronal cultures reflect the heterogeneous nature of the dorsal and median raphe nuclei, providing a platform for exploring the association of serotonergic neuron subpopulations with neuropsychiatric disorders.

JOURNAL OF NEURAL TRANSMISSION (2021)

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Article Clinical Neurology

hiPSCs for predictive modelling of neurodegenerative diseases: dreaming the possible

Pia Rivetti di Val Cervo et al.

Summary: Human induced pluripotent stem cells (hiPSCs) were first generated in 2007, but their full translational potential has not yet been realized. Potential applications in neurology, especially for studying neurodegenerative diseases, have been hindered by challenges in scalability, reproducibility and quality of disease modeling using hiPSCs. Integration of in vitro experimental data with clinical data could lead to predictive disease modeling in the field of precision medicine.

NATURE REVIEWS NEUROLOGY (2021)

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Article Cell & Tissue Engineering

Enhanced differentiation of human induced pluripotent stem cells toward the midbrain dopaminergic neuron lineage through GLYPICAN-4 downregulation

Serena Corti et al.

Summary: Downregulation of GPC4 in human induced pluripotent stem cells (hiPSC) enhances their differentiation potential into ventral midbrain dopaminergic (VMDA) neuron progenitors, while maintaining self-renewal and pluripotency in vitro and reducing tumorigenesis risk in vivo. This approach shows promise in generating VMDA neurons and establishing hiPSC lines suitable for translational applications.

STEM CELLS TRANSLATIONAL MEDICINE (2021)

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Article Cell Biology

Global transcriptome profile of the developmental principles of in vitro iPSC-to-motor neuron differentiation

Emilia Solomon et al.

Summary: The study identified and characterized gene networks triggered by chemical reprogramming iPSC into motor neurons, providing insights into the differentiation process. The findings have implications for novel therapeutic approaches in regenerative medicine.

BMC MOLECULAR AND CELL BIOLOGY (2021)

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Article Neurosciences

SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(-/-) Mice

Anne-Kathrin Lutz et al.

Summary: This study investigated human induced pluripotent stem cells from a patient with SHANK2 mutations, showing abnormalities in neuronal size, proliferation, and apoptosis. Additionally, dysregulated excitatory signaling and altered signaling pathways were observed during neuronal maturation, highlighting potential therapeutic strategies for SHANK2-related autism spectrum disorders.

FRONTIERS IN MOLECULAR NEUROSCIENCE (2021)

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Article Genetics & Heredity

Gene Regulation Analysis Reveals Perturbations of Autism Spectrum Disorder during Neural System Development

Dan Li et al.

Summary: The study compared RNA sequencing data from different cell types in ASD and normal samples, revealing that ASD occurs in the early stages of neural system development and uncovering a set of novel disease-associated genes and gene interactions, particularly highlighting the functional roles of ELF3 and the interaction between STAT1 and lncRNA ELF3-AS 1 in disease development. These findings extend our understanding of ASD and offer potential new therapeutic targets for further research.

GENES (2021)

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Article Cell & Tissue Engineering

Abnormal DNA methylation in pluripotent stem cells from a patient with Prader-Willi syndrome results in neuronal differentiation defects

Shuhei Soeda et al.

Summary: DNA methylation plays a key role in gene expression regulation, particularly in neurodevelopmental disorders like Prader-Willi syndrome (PWS). By studying iPWS cells with abnormal methylation, researchers found that these cells had defects in differentiating into ectoderm and had reduced numbers of neural stem cells and mature neurons with low expression of specific markers, suggesting the importance of methylation in neuronal differentiation.

STEM CELL RESEARCH (2021)

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Article Genetics & Heredity

Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development

J. Ellegood et al.

Summary: The study validated decreased levels of Arid1b mRNA and protein in Arid1b(+/-) mice, with altered gene expression patterns in the cerebellum. Behaviorally, the Arid1b(+/-) mice showed impairments in ultrasonic vocalizations and developmental growth, as well as deficits in motor skills and learning and memory tasks. This study highlights the importance of examining both sexes in NDDs and reveals unique neuroanatomical differences in the mouse model.

MOLECULAR AUTISM (2021)

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Article Neurosciences

Hyperexcitable Phenotypes in Induced Patients With 15q11-q13 Duplication Syndrome, a Genetic Form of Autism

James J. Fink et al.

Summary: The study investigated electrophysiological phenotypes in induced pluripotent stem cell-derived neurons from patients with Dup15q, revealing several potential mechanisms of neuronal hyperexcitability and seizure susceptibility. These findings may offer new targets for the treatment of seizures and other associated phenotypes in Dup15q.

BIOLOGICAL PSYCHIATRY (2021)

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Article Neurosciences

NRXN1α+/- is associated with increased excitability in ASD iPSC-derived neurons

Sahar Avazzadeh et al.

Summary: NRXN1α(+/-) patient-derived cortical neurons exhibit alterations in sodium currents, action potential characteristics, and transcriptomic changes related to upregulated glutamatergic synapse and ion channels/transporter activity. These changes are likely to contribute to the enhanced excitability observed in NRXN1α(+/-) cortical neurons, indicating potential therapeutic targets for ASD.

BMC NEUROSCIENCE (2021)

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Article Biochemistry & Molecular Biology

WGCNA Identifies Translational and Proteasome-Ubiquitin Dysfunction in Rett Syndrome

Florencia Haase et al.

Summary: Rett Syndrome is an X linked neurodevelopmental disorder caused by mutations in the MECP2 gene, with symptoms typically appearing between 6 to 18 months of age. Recent studies have found subtle cellular and molecular changes in neural cells before symptoms onset, suggesting global translational dysregulation may start prior to neuronal lineage commitment.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Biochemistry & Molecular Biology

Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice

Chae-Seok Lim et al.

Summary: Heterogeneity in the etiopathology of autism spectrum disorders (ASD) requires individualistic and patient-specific research. Recent progress in human-induced pluripotent stem cell (iPSC) technology provides a novel platform for studying complex neuronal phenotypes. The study found that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.

MOLECULAR PSYCHIATRY (2021)

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Article Neurosciences

Identification of neural oscillations and epileptiform changes in human brain organoids

Ranmal A. Samarasinghe et al.

Summary: This paper explores neural network and cellular complexity within human cortical and subcortical fusion organoids, revealing network dysfunction associated with Rett syndrome. The findings demonstrate the potential of brain organoids in modeling human neurological diseases and the utility in therapeutic discovery.

NATURE NEUROSCIENCE (2021)

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Review Neurosciences

Clinical and therapeutic significance of genetic variation in the GRIN gene family encoding NMDARs

Tim A. Benke et al.

Summary: Recent discoveries have shown a significant genetic variation in NMDARs, with individuals carrying GRIN variants presenting with various neurological conditions. Understanding the functional consequences of these genetic variations could lead to precision therapeutics. Animal models with human variants may uncover shared mechanisms among different neurological conditions, requiring further research and clinical trials to validate and determine the effectiveness of treatment methods.

NEUROPHARMACOLOGY (2021)

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Article Cell & Tissue Engineering

Generation of striatal neurons from human induced pluripotent stem cells by controlling extrinsic signals with small molecules

Naoya Amimoto et al.

Summary: A robust protocol was established for generating striatal medium spiny neurons from hiPSCs using small molecules under two- and three-dimensional culture conditions. This protocol provides a useful model for studying striatal development and has potential applications for regenerative medicine in treating striatum-related disorders.

STEM CELL RESEARCH (2021)

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Article Multidisciplinary Sciences

Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder

Job O. de Jong et al.

Summary: Mutations in CNTNAP2 have been linked to a specific form of Autism Spectrum Disorder. Using forebrain organoids derived from induced pluripotent stem cells of patients with this mutation, the study found that the increased volume and cell number were driven by abnormal cellular proliferation and neurogenesis, offering insights into potential therapeutic strategies for ASD.

NATURE COMMUNICATIONS (2021)

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Review Genetics & Heredity

Genotype-Phenotype Correlations in Angelman Syndrome

Lili Yang et al.

Summary: Angelman syndrome is a rare neurodevelopmental disease caused by the loss of function of the maternal copy of UBE3A. It is characterized by developmental delay, intellectual disability, lack of speech, and ataxia. Different genetic types may show different phenotypes, and understanding genotype-phenotype correlations can lead to individualized treatment options.

GENES (2021)

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Article Medicine, Research & Experimental

DSCAM/PAK1 pathway suppression reverses neurogenesis deficits in iPSC-derived cerebral organoids from patients with Down syndrome

Xiao-Yan Tang et al.

Summary: The study found that neurogenesis was significantly affected in DS patients, with reduced proliferation and expression of layer II and IV markers in cortical neurons in the subcortical regions, which may have led to the reduced size of the organoids. Additionally, suppressing the enhanced activity of the DSCAM/PAK1 pathway in DS reversed abnormal neurogenesis, increasing the size of organoids derived from DS iPSCs.

JOURNAL OF CLINICAL INVESTIGATION (2021)

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Article Genetics & Heredity

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis

Karin Weiss et al.

GENETICS IN MEDICINE (2020)

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Review Neurosciences

Zebrafish as a Model of Neurodevelopmental Disorders

Murilo S. de Abreu et al.

NEUROSCIENCE (2020)

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Article Cell & Tissue Engineering

Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability

Meiyan Wang et al.

CELL STEM CELL (2020)

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Article Cell Biology

Silencing Trisomy 21 with XIST in Neural Stem Cells Promotes Neuronal Differentiation

Jan Tomasz Czerminski et al.

DEVELOPMENTAL CELL (2020)

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Article Cell Biology

Synthetic Analyses of Single-Cell Transcriptomes from Multiple Brain Organoids and Fetal Brain

Yoshiaki Tanaka et al.

CELL REPORTS (2020)

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Article Oncology

DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors

Loora Laan et al.

CLINICAL EPIGENETICS (2020)

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Article Genetics & Heredity

TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling

Pauline Martin et al.

MOLECULAR AUTISM (2020)

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Article Multidisciplinary Sciences

Arid1b haploinsufficiency in parvalbumin- or somatostatin-expressing interneurons leads to distinct ASD-like and ID-like behavior

Amanda L. Smith et al.

SCIENTIFIC REPORTS (2020)

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Article Cell Biology

Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Ubiquitination in Rett Syndrome

Deivid C. Rodrigues et al.

CELL REPORTS (2020)

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Article Genetics & Heredity

Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors

Suzy Varderidou-Minasian et al.

MOLECULAR AUTISM (2020)

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Article Neurosciences

A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y

Thien A. Nguyen et al.

NEURON (2020)

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Article Neurosciences

Haploinsufficiency of Tsc2 Leads to Hyperexcitability of Medial Prefrontal Cortex via Weakening of Tonic GABAB Receptor-mediated Inhibition

Davide Bassetti et al.

CEREBRAL CORTEX (2020)

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Article Biochemistry & Molecular Biology

AAV-mediated FOXG1 gene editing in human Rett primary cells

Susanna Croci et al.

EUROPEAN JOURNAL OF HUMAN GENETICS (2020)

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Article Genetics & Heredity

IGF-1 treatment causes unique transcriptional response in neurons from individuals with idiopathic autism

Sara B. Linker et al.

MOLECULAR AUTISM (2020)

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Article Biochemistry & Molecular Biology

Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons

Yangfei Xiang et al.

MOLECULAR CELL (2020)

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Review Neurosciences

Modelling Learning and Memory in Drosophila to Understand Intellectual Disabilities

Vittoria Mariano et al.

NEUROSCIENCE (2020)

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Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice

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Avoiding cytotoxicity of transposases by dose-controlled mRNA delivery

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NUCLEIC ACIDS RESEARCH (2011)

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Isogenic Pairs of Wild Type and Mutant Induced Pluripotent Stem Cell (iPSC) Lines from Rett Syndrome Patients as In Vitro Disease Model

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PLOS ONE (2011)

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Review Biology

Immunological considerations for embryonic and induced pluripotent stem cell banking

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PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES (2011)

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Investigating synapse formation and function using human pluripotent stem cell-derived neurons

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2011)

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Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2011)

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Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors

Hiroshi Ban et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2011)

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Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2011)

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Oxidative stress occurs early in Down syndrome pregnancy: A redox proteomics analysis of amniotic fluid

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PROTEOMICS CLINICAL APPLICATIONS (2011)

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Meta-analysis of the heterogeneity of X chromosome inactivation in human pluripotent stem cells

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STEM CELL RESEARCH (2011)

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COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY (2011)

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The tumorigenicity of human embryonic and induced pluripotent stem cells

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NATURE REVIEWS CANCER (2011)

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Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2010)

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Comparative transfection of DNA into primary and transformed mammalian cells from different lineages

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BMC BIOTECHNOLOGY (2010)

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A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells

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Pluripotency and Cellular Reprogramming: Facts, Hypotheses, Unresolved Issues

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Female Human iPSCs Retain an Inactive X Chromosome

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Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified mRNA

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Age-dependent neuroectodermal differentiation capacity of human mesenchymal stromal cells: limitations for autologous cell replacement strategies

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Gene-delivery systems for iPS cell generation

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EXPERT OPINION ON BIOLOGICAL THERAPY (2010)

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Exploring refined conditions for reprogramming cells by recombinant Oct4 protein

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Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down's syndrome

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Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in a mutant mouse model of Rett syndrome

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Innate Immune Suppression Enables Frequent Transfection with RNA Encoding Reprogramming Proteins

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Oct4-Induced Pluripotency in Adult Neural Stem Cells

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Hypoxia Enhances the Generation of Induced Pluripotent Stem Cells

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Generation of Human Induced Pluripotent Stem Cells by Direct Delivery of Reprogramming Proteins

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Transgene expression of transfected supercoiled plasmid DNA concatemers in mammalian cells

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Direct reprogramming of human neural stem cells by OCT4

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piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells

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Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome

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Clone- and Gene-Specific Aberrations of Parental Imprinting in Human Induced Pluripotent Stem Cells

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Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells

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Comparison between Sendai virus and adenovirus vectors to transduce HIV-1 genes into human dendritic cells

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Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome

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Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2

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Behavioral and anatomical abnormalities in Mecp2 mutant mice:: A model for Rett syndrome

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Combination of bFGF, heparin and laminin induce the generation of dopaminergic neurons from rat neural stem cells both in vitro and in vivo

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Evidence for abnormal early development in a mouse model of Rett syndrome

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Gene expression changes in long term expanded human neural progenitor cells passaged by chopping lead to loss of neurogenic potential in vivo

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Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

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A ROCK inhibitor permits survival of dissociated human embryonic stem cells

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Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors

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CELL (2006)

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Necdin promotes GABAergic neuron differentiation in cooperation with Dlx homeodomain proteins

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Neural subtype specification from embryonic stem cells

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Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome

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Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome

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NEUROBIOLOGY OF DISEASE (2006)

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A capsid-modified helper-dependent adenovirus vector containing the β-globin locus control region displays a nonrandom integration pattern and allows stable, erythroid-specific gene expression

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Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett Syndrome

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2005)

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Immune responses to adeno-associated virus vectors

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CURRENT GENE THERAPY (2005)

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Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice

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JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY (2005)

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Letter Biochemistry & Molecular Biology

Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients

J Yan et al.

MOLECULAR PSYCHIATRY (2005)

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X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family

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The root-specific glutamate decarboxylase (GAD1) is essential for sustaining GABA levels in Arabidopsis

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PLANT MOLECULAR BIOLOGY (2004)

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Review Biotechnology & Applied Microbiology

Sendai virus vectors as an emerging negative-strand RNA viral vector system

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Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism

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Role of histone H3 lysine 27 methylation in X inactivation

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Homologous recombination in human embryonic stem cells

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Magnetofection: Enhancing and targeting gene delivery with superparamagnetic nanoparticles and magnetic fields

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Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo

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GENE THERAPY (2002)

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Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome

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HUMAN MOLECULAR GENETICS (2001)

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Genomic integration and gene expression by a modified adenoviral vector

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NATURE BIOTECHNOLOGY (2000)

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