scholarly journals High behavioural variability mediated by altered neuronal excitability in auts2 mutant zebrafish

2020 ◽  
Author(s):  
Urvashi Jha ◽  
Igor Kondrychyn ◽  
Vladimir Korzh ◽  
Vatsala Thirumalai
Keyword(s):  
Neural Development ◽  
Neuronal Excitability ◽  
Neural Circuit ◽  
Escape Behavior ◽  
Autism Spectrum ◽  
Large Trial ◽  
Behavioral Variability ◽  
Clear Understanding ◽  
Mauthner Neurons ◽  
Autism Susceptibility

AbstractAutism spectrum disorders (ASDs) are characterized by abnormal behavioral traits arising from neural circuit dysfunction. While a number of genes have been implicated in ASDs, in most cases, a clear understanding of how mutations in these genes lead to circuit dysfunction and behavioral abnormality is absent. The autism susceptibility candidate 2 (AUTS2) gene is one such gene, associated with ASDs, intellectual disability and a range of other neurodevelopmental conditions. Yet, the function of AUTS2 in neural development and circuit function is not at all known. Here, we undertook functional analysis of Auts2a, the main homolog of AUTS2 in zebrafish, in the context of the escape behavior. Escape behavior in wild type zebrafish is critical for survival and is therefore, reliable, rapid, and has well-defined kinematic properties. Auts2a−/− zebrafish are viable, have normal gross morphology and can generate escape behavior with normal kinematics. However, the behavior is unreliable and delayed, with high trial-to-trial variability in the latency. We demonstrate that this is due to the reduced excitability of Mauthner neurons resulting in unreliable firing with stimuli that normally elicit the escape response. Combined with previous studies that show Auts2-regulation of the transcription of ion channel proteins, our results suggest that Auts2 sets the excitability of neurons by activating a set transcriptional program.Significance statementAUTS2 is one among recently identified autism susceptibility candidate genes, whose function in neuronal circuits is unclear. Using zebrafish as a model organism, we probe the function of Auts2a (homolog of mammalian AUTS2) at the cellular, network and behavioral levels. The escape behavior of Auts2a mutant zebrafish is highly variable with normal short latency escapes, long latency escapes and total failures across trials in the same fish. This occurs because neuronal excitability is inappropriately set in the Mauthner neurons of mutants leading to the large trial-to-trial variability in responses. The behavioral variability is fully explained by variability in firing action potentials in the Mauthner neuron, providing an integrative understanding of how behavioral variability arises from mutations at the genetic level.

scholarly journals The role of CPEB family proteins in the nervous system function in the norm and pathology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eugene Kozlov ◽  
Yulii V. Shidlovskii ◽  
Rudolf Gilmutdinov ◽  
Paul Schedl ◽  
Mariya Zhukova
Keyword(s):  
Nervous System ◽  
Gene Regulation ◽  
Neural Development ◽  
Fragile X ◽  
Autism Spectrum ◽  
Mrna Transport ◽  
Ribonucleoprotein Complexes ◽  
Posttranscriptional Gene Regulation ◽  
Nervous System Function ◽  
Functional Features

AbstractPosttranscriptional gene regulation includes mRNA transport, localization, translation, and regulation of mRNA stability. CPEB (cytoplasmic polyadenylation element binding) family proteins bind to specific sites within the 3′-untranslated region and mediate poly- and deadenylation of transcripts, activating or repressing protein synthesis. As part of ribonucleoprotein complexes, the CPEB proteins participate in mRNA transport and localization to different sub-cellular compartments. The CPEB proteins are evolutionarily conserved and have similar functions in vertebrates and invertebrates. In the nervous system, the CPEB proteins are involved in cell division, neural development, learning, and memory. Here we consider the functional features of these proteins in the nervous system of phylogenetically distant organisms: Drosophila, a well-studied model, and mammals. Disruption of the CPEB proteins functioning is associated with various pathologies, such as autism spectrum disorder and brain cancer. At the same time, CPEB gene regulation can provide for a recovery of the brain function in patients with fragile X syndrome and Huntington's disease, making the CPEB genes promising targets for gene therapy.

scholarly journals Role of Exclusive Breastfeeding in Conferring Protection in Children At-Risk for Autism Spectrum Disorder: Results from a Sibling Case–control Study

2018 ◽  
Vol 09 (01) ◽  
pp. 132-136 ◽  
Author(s):  
Harshini Manohar ◽  
Madhavapuri Pravallika ◽  
Preeti Kandasamy ◽  
Venkatesh Chandrasekaran ◽  
Ravi Philip Rajkumar
Keyword(s):  
Neural Development ◽  
Exclusive Breastfeeding ◽  
Feeding Practices ◽  
Autism Spectrum ◽  
Gut Microflora ◽  
Typically Developing ◽  
Lower Odds ◽  
Children With Asd ◽  
Typically Developing Siblings

ABSTRACTBackground: Gut microflora influences neural development through complex mechanisms. Feeding practices, especially breastfeeding influence gut microbiome and thereby play a pivotal role in immune and neural development. Current understandings of the role of healthy distal gut microflora in the development of immune and neural systems provide insights into immunological mechanisms as one of the possible etiologies in autism spectrum disorder (ASD). Studies have shown that optimal breastfeeding is associated with lower odds of being at-risk for ASD and children with ASD are suboptimally breastfed. Methods: The feeding practices of children with ASD (n = 30) was compared to their typically developing siblings as matched controls (n = 30). Information regarding feeding practices was collected from mothers through a semi-structured questionnaire. Results: About 43.3% of children with ASD received exclusive breastfeeding, whereas 76.7% of their typically developing siblings were exclusively breastfed. Exclusive breastfeeding was associated with lower odds for ASD (odds ratio [OR] = 0.166; 95% confidence interval [CI] = 0.025–0.65), while early introduction of top feeds was associated with higher odds (OR = 6; 95% CI = 1.33–55.19). Difficulties in breastfeeding were attributed to child-related factors in 13.2% of the children. Conclusion: Children with ASD are suboptimally breastfed compared to their typically developing siblings. Exclusive breastfeeding may confer protection in vulnerable children. Further studies on larger prospective sample are required to establish the association.

Cyclic AMP Mediates Serotonin-Induced Synaptic Enhancement of Lateral Giant Interneuron of the Crayfish

2005 ◽  
Vol 94 (4) ◽  
pp. 2644-2652 ◽  
Author(s):  
Makoto Araki ◽  
Toshiki Nagayama ◽  
Jordanna Sprayberry
Keyword(s):  
Biogenic Amines ◽  
Time Course ◽  
Neural Circuit ◽  
Escape Behavior ◽  
Direct Injection ◽  
Phosphodiesterase Inhibitor ◽  
Sensory Stimulation ◽  
Simultaneous Application ◽  
Camp Analogue ◽  
Repetitive Sensory Stimulation

The lateral giant (LG)-mediated escape behavior of the crayfish habituates readily on repetitive sensory stimulation. Recent studies suggested that the biogenic amines serotonin and octopamine modulate the time course of recovery and/or re-depression of the LG response after habituation. However, little is known of how serotonin and octopamine effect LG habituation and what second-messenger cascades they may activate. To investigate the effect of biogenic amines on LG habituation, serotonin and octopamine were superfused before presenting repetitive sensory stimulation. Serotonin and octopamine increased the number of stimuli needed to habituate the LG response. Their effects were mimicked by mixed application of a cAMP analogue [8-(4-chlorophenylthio)-cAMP (CPT-cAMP)] and a phosphodiesterase inhibitor [3-isobutyl-1-methylxanthine (IBMX)] but not by a cGMP analogue (8-bromoguanosine 3′,5′-cyclic monophosphate). Perfusion of the adenylate cyclase inhibitor (SQ22536) abolished the effect of serotonin but not that of octopamine. To investigate the site of action of each biogenic amines in the neural circuit meditating LG escape, the effect of drugs on directly and indirectly elicited postsynaptic potentials in LG was investigated. Serotonin, octopamine, and a mixture of CPT-cAMP and IBMX increased both the direct and indirect synaptic inputs. Simultaneous application of SQ22536 abolished the effect of serotonin on both inputs but did not block the effect of octopamine. Direct injection of the cAMP analogue (Sp-isomer of adenosine-3′,5′-cyclic monophosphorothioate) into LG increased both the direct and indirect inputs to LG. These results indicate that serotonin mediates an increase in cAMP levels in LG, but octopamine acts independently of cAMP and cGMP.

scholarly journals Bridging physiological and perceptual views of autism by means of sampling-based Bayesian inference

2021 ◽  
pp. 1-27
Author(s):  
Rodrigo Echeveste ◽  
Enzo Ferrante ◽  
Diego H. Milone ◽  
Inés Samengo
Keyword(s):  
Autism Spectrum Disorder ◽  
Neural Circuit ◽  
Autism Spectrum ◽  
Physiological Level ◽  
Cortical Dynamics ◽  
Significant Challenge ◽  
Characteristic Features ◽  
Neural Variability ◽  
Two Sides ◽  
Different Levels

Abstract Theories for autism spectrum disorder (ASD) have been formulated at different levels: ranging from physiological observations to perceptual and behavioral descriptions. Understanding the physiological underpinnings of perceptual traits in ASD remains a significant challenge in the field. Here we show how a recurrent neural circuit model which was optimized to perform sampling-based inference and displays characteristic features of cortical dynamics can help bridge this gap. The model was able to establish a mechanistic link between two descriptive levels for ASD: a physiological level, in terms of inhibitory dysfunction, neural variability and oscillations, and a perceptual level, in terms of hypopriors in Bayesian computations. We took two parallel paths: inducing hypopriors in the probabilistic model, and an inhibitory dysfunction in the network model, which lead to consistent results in terms of the represented posteriors, providing support for the view that both descriptions might constitute two sides of the same coin.

scholarly journals Changes in the Fluorescence Tracking of NaV1.6 Protein Expression in a BTBR T+Itpr3tf/J Autistic Mouse Model

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Musaad A. Alshammari ◽  
Mohammad R. Khan ◽  
Fawaz Alasmari ◽  
Abdulaziz O. Alshehri ◽  
Rizwan Ali ◽  
...  
Keyword(s):  
Mouse Model ◽  
Western Blot ◽  
Neuronal Excitability ◽  
Autism Spectrum ◽  
Wild Type ◽  
Western Blot Assay ◽  
Critical Determinant ◽  
Molecular Features ◽  
Voltage Gated Sodium Channels ◽  
Wild Type Control

The axon initial segment (AIS), the site of action potential initiation in neurons, is a critical determinant of neuronal excitability. Growing evidence indicates that appropriate recruitment of the AIS macrocomplex is essential for synchronized firing. However, disruption of the AIS structure is linked to the etiology of multiple disorders, including autism spectrum disorder (ASD), a condition characterized by deficits in social communication, stereotyped behaviors, and very limited interests. To date, a complete understanding of the molecular components that underlie the AIS in ASD has remained elusive. In this research, we examined the AIS structure in a BTBR T+Itpr3tf/J mouse model (BTBR), a valid model that exhibits behavioral, electrical, and molecular features of autism, and compared this to the C57BL/6J wild-type control mouse. Using Western blot studies and high-resolution confocal microscopy in the prefrontal frontal cortex (PFC), our data indicate disrupted expression of different isoforms of the voltage-gated sodium channels (NaV) at the AIS, whereas other components of AIS such as ankyrin-G and fibroblast growth factor 14 (FGF14) and contactin-associated protein 1 (Caspr) in BTBR were comparable to those in wild-type control mice. A Western blot assay showed that BTBR mice exhibited a marked increase in different sodium channel isoforms in the PFC compared to wild-type mice. Our results provide potential evidence for previously undescribed mechanisms that may play a role in the pathogenesis of autistic-like phenotypes in BTBR mice.

scholarly journals Neuritin Up-regulates Kv4.2 α-Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway

2016 ◽  
Vol 291 (33) ◽  
pp. 17369-17381 ◽  
Author(s):  
Jin-jing Yao ◽  
Qian-Ru Zhao ◽  
Dong-Dong Liu ◽  
Chi-Wing Chow ◽  
Yan-Ai Mei
Keyword(s):  
Signaling Pathway ◽  
Neural Development ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Neuronal Excitability ◽  
Outward Current ◽  
Nuclear Accumulation ◽  
Luciferase Reporter ◽  
Activated T Cells ◽  
Α Subunit

Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca2+/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca2+ and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4−/− mice but not in Nfatc2−/− mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4−/− mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions.

Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly

2018 ◽  
Vol 34 (1) ◽  
pp. 471-493 ◽  
Author(s):  
George Mountoufaris ◽  
Daniele Canzio ◽  
Chiamaka L. Nwakeze ◽  
Weisheng V. Chen ◽  
Tom Maniatis
Keyword(s):  
Cell Surface ◽  
Neural Circuit ◽  
Receptive Fields ◽  
Structural Diversity ◽  
Autism Spectrum ◽  
Surface Proteins ◽  
Abnormal Behavior ◽  
Surface Code ◽  
Family Based ◽  
Circuit Assembly

The ability of neurites of individual neurons to distinguish between themselves and neurites from other neurons and to avoid self (self-avoidance) plays a key role in neural circuit assembly in both invertebrates and vertebrates. Similarly, when individual neurons of the same type project into receptive fields of the brain, they must avoid each other to maximize target coverage (tiling). Counterintuitively, these processes are driven by highly specific homophilic interactions between cell surface proteins that lead to neurite repulsion rather than adhesion. Among these proteins in vertebrates are the clustered protocadherins (Pcdhs), and key to their function is the generation of enormous cell surface structural diversity. Here we review recent advances in understanding how a Pcdh cell surface code is generated by stochastic promoter choice; how this code is amplified and read by homophilic interactions between Pcdh complexes at the surface of neurons; and, finally, how the Pcdh code is translated to cellular function, which mediates self-avoidance and tiling and thus plays a central role in the development of complex neural circuits. Not surprisingly, Pcdh mutations that diminish homophilic interactions lead to wiring defects and abnormal behavior in mice, and sequence variants in the Pcdh gene cluster are associated with autism spectrum disorders in family-based genetic studies in humans.

Increasing Behavioral Variability and Social Skill Accuracy in Children with Autism Spectrum Disorder

2018 ◽  
Vol 27 (3) ◽  
pp. 395-418 ◽  
Author(s):  
Keith C. Radley ◽  
Allison A. Battaglia ◽  
Komila Dadakhodjaeva ◽  
W. Blake Ford ◽  
Kristi Robbins
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Skill ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Behavioral Variability

scholarly journals Problems of diagnosing autism spectrum disorders in children

2020 ◽  
pp. 35-43
Author(s):  
E. A. Tkachuk ◽  
N. N. Martynovich ◽  
L. V. Rychkova ◽  
V. M. Polyakov
Keyword(s):  
Autism Spectrum Disorders ◽  
Genetic Analysis ◽  
Medical Treatment ◽  
Scientific Community ◽  
Autism Spectrum ◽  
Screening Methods ◽  
Clear Understanding ◽  
Main Method ◽  
Spectrum Disorders ◽  
Russian Medical

The review of the publications devoted to the methods of early diagnosing autism spectrum disorders (ASD) among children. The spread of this pathology causes mixed assessments in scientific community. The frequency of ASD in different countries makes up from 5 to 90 among 10,000 children and teenagers. An increase in morbidity makes the problem of diagnosing ASD among children very urgent. The main method of diagnosing is behavioral, but they allow to diagnose autism when the child is older than 1.5 years old, when medical and corrective actions are no longer effective. The prenatal diagnostics of the ASD are almost unused. The methods of genetic analysis are considered to be additional and don’t have the direct diagnostic meaning connected with the lack of clear understanding of the etiology and pathogenesis of ASD. According to Russian medical regulations children having early signs of autism can’t be defined in the age when timely medical treatment is effective. Due to this fact it was concluded that it is necessary to develop screening methods and regulations of providing medical treatment to children an teenagers having ASD.

scholarly journals CHD8 regulates the balance between proliferation and differentiation of human iPSCs in neural development

2019 ◽  
Author(s):  
Wenzhong Liu ◽  
Weilai Dong ◽  
Ellen J. Hoffman ◽  
Thomas V. Fernandez ◽  
Abha R. Gupta
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Neural Development ◽  
Neural Differentiation ◽  
Neural Progenitor Cells ◽  
Autism Spectrum ◽  
Neural Cells ◽  
Neuronal Marker ◽  
Human Ipscs ◽  
M Phase

ABSTRACTBackgroundChromodomain helicase DNA-binding protein 8 (CHD8), which encodes a chromatin remodeling protein that regulates Wnt/β-catenin mediated gene expression, is one of the most strongly associated genes with autism spectrum disorder (ASD). Characterization of ASD patients with CHD8 disrupting mutations and animal and stem cell models of CHD8 deficiency suggest that CHD8 plays a role in neurodevelopment.MethodsWe generated iPSCs from the T-lymphocytes of a healthy, typically-developing human male and iPSC lines from the same source which were subjected to CRISPR/Cas9-mediated knockdown (KD) of CHD8. We subsequently derived neural progenitor cells (NPCs) and neural cells and examined the effects of CHD8 deficiency on cell proliferation and neural differentiation.ResultsWe observed that, compared to WT, CHD8 KD: (1) increased the number of iPSC colonies formed, (2) suppressed spontaneous differentiation along the edges of iPSC colonies, (3) increased the proliferation of NPCs, (4) delayed the formation of neural rosettes, (5) delayed neurite outgrowth, (6) decreased the percentage of cells in the G0/G1 phase of the cell cycle, (7) increased the percentage of cells in the G2/M phase of the cell cycle, (8) decreased presence of the neuronal marker MAP2 although not the glial marker GFAP, (9) decreased presence for the excitatory neuronal marker VGLUT1, and (10) decreased presence of the synaptic marker SYN1.ConclusionsOur results suggest that CHD8 deficiency causes alterations in the cell cycle. More specifically, CHD8 KD appears to increase cell proliferation and delay neural differentiation. This may contribute to the pathophysiology of ASD.

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