Neurobiology of Autism Spectrum Disorders

2017 ◽  
Vol 41 (S1) ◽  
pp. S45-S46
Author(s):  
T.M. Sheldrick-Michel ◽  
B.T. Morten ◽  
B. Niels ◽  
I. Mirolyuba
Keyword(s):  
Autism Spectrum Disorders ◽  
High Throughput Screening ◽  
Drug Testing ◽  
Developmental Stages ◽  
Disease Model ◽  
Behavioral Flexibility ◽  
Autism Spectrum ◽  
Spectrum Disorders

Autism Spectrum Disorders (ASD) is a group of neurodevelopmental disorders with heterogeneous etiology characterized by deficits in social cognition, communication, and behavioral flexibility. Disturbances on molecular and cellular level in early brain development incl. intercellular communication, an unbalanced ratio between certain neuronal populations and maturation/differentiation process, oxidative stress, happening in embryonal stages, might be promising candidates to explain the development of autistic symptoms.In order to get a deeper understanding of these processes, valid “disease models” are pivotal. A new cutting edge technique, named brain organoids, has been highlighted as a promising candidate for obtaining a better “disease model”.Brain organoids derived from patients induced pluripotent stem cells (iPSC) follow in vivo timeline development; they also have the ability to recreate the right complexity of the brains, developmental stages. On the cellular and gene expression level, organoids demonstrate a high similarity to the developing brain in vivo and can therefore recapitulate early stages of the neurogenesis. To date organoids are the most relevant cellular in vitro platform for the understanding of the mechanisms behind ADS pathology. Investigations of “mini brains” at different time points in their development will give a wider and more detailed picture of the disease dynamic and thus the development of therapeutic and prevention strategies. It is a tool that can be used for effective high throughput screening of chemical compounds as potential drugs (“in sphero” drug testing). Organoids are a good modeling system for elucidating the role of epigenetic and environmental factors for development of ASD.Disclosure of interestThe authors declare that they have no competing interest.

scholarly journals Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1376
Author(s):  
Alba Pensado-López ◽  
Sara Veiga-Rúa ◽  
Ángel Carracedo ◽  
Catarina Allegue ◽  
Laura Sánchez
Keyword(s):  
Autism Spectrum Disorders ◽  
Autism Spectrum ◽  
Experimental Models ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Complex Disorder ◽  
Spectrum Disorders ◽  
Associated Risk Factors

Autism Spectrum Disorders (ASD) affect around 1.5% of the global population, which manifest alterations in communication and socialization, as well as repetitive behaviors or restricted interests. ASD is a complex disorder with known environmental and genetic contributors; however, ASD etiology is far from being clear. In the past decades, many efforts have been put into developing new models to study ASD, both in vitro and in vivo. These models have a lot of potential to help to validate some of the previously associated risk factors to the development of the disorder, and to test new potential therapies that help to alleviate ASD symptoms. The present review is focused on the recent advances towards the generation of models for the study of ASD, which would be a useful tool to decipher the bases of the disorder, as well as to conduct drug screenings that hopefully lead to the identification of useful compounds to help patients deal with the symptoms of ASD.

scholarly journals MECP2 duplication and mutations impair NSCs differentiation via miR-197 regulated ADAM10

2018 ◽  
Author(s):  
Yu-Meng Wang ◽  
Yu-Fang Zheng ◽  
Si-Yu Yang ◽  
Zhang-Min Yang ◽  
Lin-Na Zhang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Notch Signaling ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Autism Spectrum ◽  
Embryonic Brain ◽  
Missense Mutations ◽  
Spectrum Disorders

AbstractHow MECP2 (Methyl-CpG-binding protein 2) duplication affects cortex development remains elusive. We found that elevated MeCP2 expression promotes neurogenesis during cortex development in Tg(MECP2) mouse brain. Ectopic expression of MeCP2 in NPCs inhibits ADAM10 and hence compromises the NOTCH pathway during NPC differentiation. MeCP2 up-regulates miR-197 to down-regulate ADAM10. The enhanced NPC differentiation/migration in Tg(MECP2) embryonic brain can be repressed by overexpression of ADAM10 or a miR-197 inhibitor.Consistently, the reduced neurogenesis induced by three rare MeCP2 missense mutations (H371R, E394K, G428S) identified in a Han Chinese autism spectrum disorders (ASD) cohort, can be reversed by miR-197 both in vitro and in vivo. Our results revealed that a regulatory axis involving MeCP2, miR-197, ADAM10, and NOTCH signaling is critical for neurogenesis, which is affected by both MeCP2 duplication and mutation.

scholarly journals Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jason L. He ◽  
Georg Oeltzschner ◽  
Mark Mikkelsen ◽  
Alyssa Deronda ◽  
Ashley D. Harris ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Strong Support ◽  
Empirical Support ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Resonance Spectroscopy ◽  
Primary Sensorimotor Cortex ◽  
Spectrum Disorders ◽  
Inhibitory Signaling

AbstractIndividuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

scholarly journals Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders

2015 ◽  
Vol 112 (48) ◽  
pp. 14805-14810 ◽  
Author(s):  
Thuy N. Vien ◽  
Amit Modgil ◽  
Armen M. Abramian ◽  
Rachel Jurd ◽  
Joshua Walker ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Membrane Stability ◽  
Receptor Subtypes ◽  
Neuronal Inhibition ◽  
Spectrum Disorders ◽  
Spine Structure

Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the β3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in β3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of β3-containing GABAARs may directly contribute to the pathophysiology of ASDs.

scholarly journals Theory of Mind Deficit versus Faulty Procedural Memory in Autism Spectrum Disorders

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Miguel Ángel Romero-Munguía
Keyword(s):  
Autism Spectrum Disorders ◽  
Theory Of Mind ◽  
Cognitive Skills ◽  
Behavioral Flexibility ◽  
Poor Performance ◽  
Executive Dysfunction ◽  
Procedural Memory ◽  
Autism Spectrum ◽  
Central Coherence ◽  
Spectrum Disorders

Individuals with autism spectrum disorders (ASD) have impairments in social interaction, communicative capacity, and behavioral flexibility (core triad). Three major cognitive theories (theory of mind deficit, weak central coherence, and executive dysfunction) seem to explain many of these impairments. Currently, however, the empathizing-systemizing (a newer version of the theory of mind deficit account) and mnesic imbalance theories are the only ones that attempt to explain all these core triadic symptoms of ASD On the other hand, theory of mind deficit in empathizing-systemizing theory is the most influential account for ASD, but its counterpart in the mnesic imbalance theory, faulty procedural memory, seems to occur earlier in development; consequently, this might be a better solution to the problem of the etiology of ASD, if it truly meets the precedence criterion. Hence, in the present paper I review the reasoning in favor of the theory of mind deficit but with a new interpretation based on the mnesic imbalance theory, which posits that faulty procedural memory causes deficits in several cognitive skills, resulting in poor performance in theory of mind tasks.

scholarly journals Cholesterol in autism spectrum disorders

2021 ◽  
Author(s):  
Rafael Franco ◽  
Rafael Rivas-Santisteban ◽  
Gemma Navarro ◽  
Irene Reyes-Resina
Keyword(s):  
Autism Spectrum Disorders ◽  
Neural Development ◽  
Developmental Stages ◽  
Neurological Diseases ◽  
Autism Spectrum ◽  
New Therapeutic Approaches ◽  
Degree Of Disability ◽  
The Central Nervous System ◽  
Spectrum Disorders ◽  
The Look

The autism spectrum disorder (ASD) comprises a series of neurological diseases that share serious alterations of the development of the central nervous system. The degree of disability may vary so that Asperger’s may have a relatively normal life and get positions of responsibility in corporations and even in Governments, whereas other ASD sufferers are fully dependent on caregivers and have serious cognitive deficits. Although the first cases of autism were detected by looking at failures in metabolism, e.g., phenylketonuria, to later identify the faulty gene, today the trend is the opposite, first obtaining the exome and minimizing the look for altered parameters in blood, urine, etc. Cholesterol is key for neural development as it is not able to cross the blood brain barrier. Therefore, any gene or environmental factor that affects cholesterol synthesis will impact early developmental stages eventually leading to a disease within the autism spectrum and/or schizophrenia. This review provides data of the relevance of cholesterol dyshomeostasis in autism spectrum disorders. Determining biochemical parameters in body fluids should help to provide new therapeutic approaches in some cases of autism.

scholarly journals A 3D Heterotypic Multicellular Tumor Spheroid Assay Platform to Discriminate Drug Effects on Stroma versus Cancer Cells

2019 ◽  
Vol 25 (3) ◽  
pp. 265-276
Author(s):  
Zoe Weydert ◽  
Madhu Lal-Nag ◽  
Lesley Mathews-Greiner ◽  
Christoph Thiel ◽  
Henrik Cordes ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Stromal Cells ◽  
High Throughput Screening ◽  
Drug Testing ◽  
Therapeutic Window ◽  
Multicellular Tumor Spheroid ◽  
Cytotoxic Effects ◽  
Primary Tumors

Three-dimensional (3D) cell culture models are thought to mimic the physiological and pharmacological properties of tissues in vivo more accurately than two-dimensional cultures on plastic dishes. For the development of cancer therapies, 3D spheroid models are being created to reflect the complex histology and physiology of primary tumors with the hopes that drug responses will be more similar to and as predictive as those obtained in vivo. The effect of additional cell types in tumors, such as stromal cells, and the resulting heterotypic cell–cell crosstalk can be investigated in these heterotypic 3D cell cultures. Here, a high-throughput screening-compatible drug testing platform based on 3D multicellular spheroid models is described that enables the parallel assessment of toxicity on stromal cells and efficacy on cancer cells by drug candidates. These heterotypic microtissue tumor models incorporate NIH3T3 fibroblasts as stromal cells that are engineered with a reporter gene encoding secreted NanoLUC luciferase. By tracking the NanoLUC signal in the media over time, a time-related measurement of the cytotoxic effects of drugs on stromal cells over the cancer cells was possible, thus enabling the identification of a therapeutic window. An in vitro therapeutic index parameter is proposed to help distinguish and classify those compounds with broad cytotoxic effects versus those that are more selective at targeting cancer cells.

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