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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
J. Ellegood ◽  
S. P. Petkova ◽  
A. Kinman ◽  
L. R. Qiu ◽  
A. Adhikari ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Ex Vivo ◽  
Chromatin Modification ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Altered Expression ◽  
Developmental Growth ◽  
And Behavior

Abstract Background One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. Methods A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. Results We validated decreased Arid1b mRNA and protein in Arid1b+/− mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b+/− cerebellum. During neonatal development, Arid1b+/− mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b+/− mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b+/− mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male–female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b+/− mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. Limitations The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. Conclusions This study represents a full validation and investigation of a novel model of Arid1b+/− haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

scholarly journals Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

2020 ◽  
Author(s):  
Jacob Ellegood ◽  
Stela P Petkova ◽  
Adrienne Kinman ◽  
Lily R Qiu ◽  
Ayanna Wade ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Ex Vivo ◽  
Chromatin Modification ◽  
Autism Spectrum ◽  
Social Deficits ◽  
Repetitive Behaviours ◽  
Developmental Growth ◽  
Reported Data ◽  
Full Investigation

Abstract Background - One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B (ARID1B) , a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. Methods - A novel preclinical mouse model of Arid1b deficiency was created validated to characterize and define neuroanatomical, behavioural and tran­scriptional phenotypes. Neuroanatomy was assess ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones.Results - Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume. In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, during neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. As adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. Limitations – The behaviour and the neuroimaging analysis were done on separate cohorts of mice, which does not allow a direct correlation between the imaging and behavioural findings. Conclusions – This study represents a full investigation of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

scholarly journals Inhibition of TRPV4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

2021 ◽  
Author(s):  
Stamatina Tzanoulinou ◽  
Stefano Musardo ◽  
Alessandro Contestabile ◽  
Sebastiano Bariselli ◽  
Giulia Casarotto ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Ex Vivo ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Neurodevelopmental Disease ◽  
Environmental Interactions ◽  
Potential Risk Factors

Autism spectrum disorder is a neurodevelopmental disease characterized by social deficits and repetitive behaviors. The high heterogeneity of the disease may be explained by gene and environmental interactions and potential risk factors include immune dysfunctions and immune-mediated co-morbidities. Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioural deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the NAc promotes D1R-MSN hyperexcitability and upregulates Trpv4 to impair social behaviour. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce inflammatory response, showed similar circuit and behavioural alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

scholarly journals Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

2022 ◽  
Author(s):  
Stamatina Tzanoulinou ◽  
Stefano Musardo ◽  
Alessandro Contestabile ◽  
Sebastiano Bariselli ◽  
Giulia Casarotto ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Transient Receptor Potential Vanilloid ◽  
Acute Inflammatory Response ◽  
Social Deficits ◽  
Neurodevelopmental Disease

AbstractMutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3+/− mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

scholarly journals Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring

2021 ◽  
Vol 15 ◽  
Author(s):  
Jianbo Liu ◽  
Yujie Liang ◽  
Xing Jiang ◽  
Jianchang Xu ◽  
Yumeng Sun ◽  
...  
Keyword(s):  
Maternal Diabetes ◽  
Autism Spectrum ◽  
Oxytocin Receptor ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Epigenetic Methylation ◽  
Mouse Study

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impaired skills in social interaction and communication in addition to restricted and repetitive behaviors. Many different factors may contribute to ASD development; in particular, oxytocin receptor (OXTR) deficiency has been reported to be associated with ASD, although the detailed mechanism has remained largely unknown. Epidemiological study has shown that maternal diabetes is associated with ASD development. In this study, we aim to investigate the potential role of OXTR on maternal diabetes-mediated social deficits in offspring. Our in vitro study of human neuron progenitor cells showed that hyperglycemia induces OXTR suppression and that this suppression remains during subsequent normoglycemia. Further investigation showed that OXTR suppression is due to hyperglycemia-induced persistent oxidative stress and epigenetic methylation in addition to the subsequent dissociation of estrogen receptor β (ERβ) from the OXTR promoter. Furthermore, our in vivo mouse study showed that maternal diabetes induces OXTR suppression; prenatal OXTR deficiency mimics and potentiates maternal diabetes-mediated anxiety-like behaviors, while there is less of an effect on autism-like behaviors. Additionally, postnatal infusion of OXTR partly, while infusion of ERβ completely, reverses maternal diabetes-induced social deficits. We conclude that OXTR may be an important factor for ASD development and that maternal diabetes-induced suppression of oxytocin receptor contributes to social deficits in offspring.

scholarly journals Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

2020 ◽  
Author(s):  
J. Ellegood ◽  
S.P. Petkova ◽  
A. Kinman ◽  
L.R. Qiu ◽  
A. Wade ◽  
...  
Keyword(s):  
Health Anxiety ◽  
Chromatin Modification ◽  
Autism Spectrum ◽  
Social Deficits ◽  
Neonatal Development ◽  
Neural Connections ◽  
Developmental Growth ◽  
Delayed Emergence ◽  
And Control ◽  
Full Investigation

AbstractOne of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and genes that regulate chromatin modify and control events regulating the formation of neural connections. AT-Rich Interactive Domain 1B (ARID1B), a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. For this work, a novel preclinical mouse model of Arid1b deficiency was created and molecularly validated to characterize and define neuroanatomical, behavioural and transcriptional phenotypes. Brains of adult Arid1b+/- mice had a smaller cerebellum along with a larger hippocampus and corpus callosum. In addition, a notable sex dependence was observed throughout development; males had an early emergence of the neuroanatomical phenotype around postnatal day 7, whereas females had a delayed emergence of the phenotype around postnatal day 40. Behavioural assays relevant to NDD were conducted during neonatal development and adulthood to evaluate general health, anxiety-like, motor, cognitive, and social behaviours in Arid1b+/- mice. During neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. As adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but surprisingly not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. This study represents a full investigation of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

Screening and Diagnosis of Autism Spectrum Disorder via Assistive Tools

2022 ◽  
pp. 1-21
Author(s):  
Gurkan Tuna ◽  
Ayşe Tuna
Keyword(s):  
Autism Spectrum Disorder ◽  
Random Forest ◽  
Performance Metrics ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
K Nearest Neighbors ◽  
Medical Test ◽  
And Behavior

Autism spectrum disorder (ASD) is a challenging developmental condition that involves restricted and/or repetitive behaviors and persistent challenges in social interaction and speech and nonverbal communication. There is not a standard medical test used to diagnose ASD; therefore, diagnosis is made by looking at the child's developmental history and behavior. In recent years, due to the increase in diagnosed cases of ASD, researchers proposed software-based tools to aid in and expedite the diagnosis. Considering the fact that most of these tools rely on the use of classifiers, in study, random forest, decision tree, k-nearest neighbors, and zero rule algorithms are used as classifiers, and their performances are compared using well-known performance metrics. As proven in the study, random forest algorithm can provide higher accuracy than the others in the classification of ASD and can be integrated into a computer- or humanoid-robot-based system for automated prescreening and diagnosis of ASD in preschool children groups.

scholarly journals Altered expression of mitochondrial electron transport chain proteins and improved myocardial energetic state during late ischemic preconditioning

2012 ◽  
Vol 302 (10) ◽  
pp. H1974-H1982 ◽  
Author(s):  
Jesús A. Cabrera ◽  
Elizabeth A. Ziemba ◽  
Robert Colbert ◽  
Lorraine B. Anderson ◽  
Willem Sluiter ◽  
...  
Keyword(s):  
Electron Transport ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
High Energy ◽  
Low Flow ◽  
In Vivo Studies ◽  
Complex Iv ◽  
Altered Expression ◽  
Energetic State

Altered expression of mitochondrial electron transport proteins has been shown in early preconditioned myocardial tissue. We wished to determine whether these alterations persist in the Second Window of Protection (SWOP) and if so, whether a favorable energetic state is facilitated during subsequent ischemia. Fourteen pigs underwent a SWOP protocol with ten 2-minute balloon inflations in the LAD artery, each separated by 2 minutes reperfusion. Twenty-four hours later, mitochondria were isolated from SWOP and SHAM pig hearts and analyzed for uncoupling protein (UCP)-2 content by western blot analysis, proteomic changes by iTRAQ® and respiration by an oxygen electrode. In parallel in vivo studies, high-energy nucleotides were obtained by transmural biopsy from anesthetized SWOP and SHAM pigs at baseline and during sustained low-flow ischemia. Compared with SHAM mitochondria, ex vivo SWOP heart tissue demonstrated increased expression of UCP-2, Complex IV (cytochrome c oxidase) and Complex V (ATPase) proteins. In comparison with SHAM pigs during in vivo conditions, transmural energetics in SWOP hearts, as estimated by the free energy of ATP hydrolysis (ΔG0), were similar at baseline but had decreased by the end of low-flow ischemia (-57.0 ± 2.1 versus -51.1 ± 1.4 kJ/mol; P < 0.05). In conclusion, within isolated mitochondria from preconditioned SWOP hearts, UCP-2 is increased and in concert with enhanced Complex IV and V proteins, imparts a favorable energetic state during low-flow ischemia. These data support the notion that mitochondrial adaptations that may reduce oxidant damage do not reduce the overall efficiency of energetics during sustained oxygen deprivation.

scholarly journals Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism

2017 ◽  
Vol 114 (30) ◽  
pp. 8119-8124 ◽  
Author(s):  
Karen J. Parker ◽  
Ozge Oztan ◽  
Robin A. Libove ◽  
Raena D. Sumiyoshi ◽  
Lisa P. Jackson ◽  
...  
Keyword(s):  
Social Functioning ◽  
Placebo Treatment ◽  
Primary Outcome Measure ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Responsiveness ◽  
Social Deficits ◽  
Double Blind ◽  
Children With Asd ◽  
Social Abilities

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients’ underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6–12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial’s primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

scholarly journals Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3-/y rat model of autism

2020 ◽  
Author(s):  
Natasha J Anstey ◽  
Vijayakumar Kapgal ◽  
Shashank Tiwari ◽  
Thomas C Watson ◽  
Anna KH Toft ◽  
...  
Keyword(s):  
Emotional Disorders ◽  
Rat Model ◽  
Ex Vivo ◽  
Transmembrane Protein ◽  
Autism Spectrum ◽  
Fear Learning ◽  
Flight Behaviour ◽  
Cellular Excitability ◽  
Lower Magnitude

SummaryMutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. Whilst examining fear in a rat model of ASD/ID lacking Nlgn3, we observed that they display a greater propensity to exhibit flight responses in contrast to classic freezing seen in wildtypes during fearful situations. Consequently, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. In ex vivo slices from Nlgn3-/y, rats, dorsal PAG (dPAG) neurons showed intrinsic hyperexcitability. Further analysis of this revealed lower magnitude in vivo dPAG stimulation evoked flight behaviour in Nlgn3-/y, rats, indicating the functional impact of the increased cellular excitability. This study provides new insight into potential pathophysiologies leading to emotional disorders in individuals with ASD.

scholarly journals The effects of maternal SSRI exposure on the serotonin system, prefrontal protein expression and behavioral development in male and female offspring rats

2020 ◽  
Author(s):  
Mo Xian Chen ◽  
Shu Cheng ◽  
Lei Lei ◽  
Chloe U Wallis ◽  
Qiang Liu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Prenatal Exposure ◽  
Ex Vivo ◽  
Physical Development ◽  
Autism Spectrum ◽  
Resonance Spectroscopy ◽  
Serotonin Level ◽  
Sprague Dawley ◽  
Genetic Syndromes

Abstract Background Prenatal exposure to selective serotonin reuptake inhibitor (SSRI), such as fluoxetine (FLX) may increase susceptibility to autism spectrum disorder (ASD). However, findings from published studies on SSRI and ASD are inconsistent. The use of a rodent model can provide a clear indication as to whether prenatal exposure to SSRIs, independent of maternal psychiatric disorders or genetic syndromes, can cause long-term behavioral and ASD-related neurobiological abnormalities in offspring. Methods FLX or normal saline (NS) was administered to pregnant Sprague-Dawley (SD) rats (FLX=30, NS=27) on gestation day 11 till birth. The resulting offspring were assessed in terms of their physical development and behavior, and underwent in vivo magnetic resonance spectroscopy ( MRS) to quantify biochemical alterations in the prefrontal cortex (PFC). Ex vivo measurements of brain serotonin level and a proteomic analysis were also undertaken. Results The offspring (male offspring in particular) of fluoxetine exposed mothers showed delayed physical development, increased anxiety and impaired social interaction. Moreover, down-regulation of 5-HT or SERT expression and up-regulation of TPH levels was observed in the PFC. We also found that prenatal FLX exposure significantly decreased NAA/tCr with 1 H-MRS in the PFC. Finally, a proteomic study revealed sex-dependent differential protein expression. ConclusionsThese findings may have translational importance suggesting that the use of SSRI medication alone in pregnant mothers may result in developmental delay and autistic-like behavior in their offspring. Our results also help to guide the choice of outcome measures in the identification of molecular and developmental mechanisms that may confer vulnerability in ASD.

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