scholarly journals Aberrant aggressive behavior in a mouse model of Angelman syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lilach Simchi ◽  
Hanoch Kaphzan
Keyword(s):  
Social Behavior ◽  
Mouse Model ◽  
Aggressive Behavior ◽  
Social Interactions ◽  
Angelman Syndrome ◽  
Case Reports ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Affiliative Behavior ◽  
Severe Difficulty

AbstractAngelman syndrome (AS) is a genetic neurodevelopmental disorder due to the absence of the E3-ligase protein, UBE3A. Inappropriate social interactions, usually hyper-sociability, is a part of that syndrome. In addition, clinical surveys and case reports describe aggressive behavior in AS individuals as a severe difficulty for caretakers. A mouse model for AS recapitulates most of the human AS phenotypes. However, very few studies utilized this mouse model for investigating affiliative social behavior, and not even a single study examined aggressive behavior. Hence, the aim of the herein study was to examine affiliative and aggressive social behavior. For that, we utilized a battery of behavioral paradigms, and performed detailed analyses of these behaviors. AS mice exhibited a unique characteristic of reduced habituation towards a social stimulus in comparison to their wild-type (WT) littermates. However, overall there were no additional marked differences in affiliative social behavior. In contrast to the mild changes in affiliative behavior, there was a striking enhanced aggression in the AS mice compared to their WT littermates. The herein findings emphasize the use of AS mouse model in characterizing and measuring inappropriate aggressive behavior, and suggests these as tools for investigating therapeutic interventions aimed at attenuating aggressive behavior.

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

2015 ◽  
Vol 112 (16) ◽  
pp. 5129-5134 ◽  
Author(s):  
Caleigh Mandel-Brehm ◽  
John Salogiannis ◽  
Sameer C. Dhamne ◽  
Alexander Rotenberg ◽  
Michael E. Greenberg
Keyword(s):  
Angelman Syndrome ◽  
Motor Coordination ◽  
Neural Circuit ◽  
Brain Activity ◽  
Neurodevelopmental Disorder ◽  
Ultrasonic Vocalizations ◽  
Therapeutic Interventions ◽  
Motor Deficits ◽  
Loss Of Function ◽  
Circuit Defects

Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder.

scholarly journals Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Monica Sonzogni ◽  
Peipei Zhai ◽  
Edwin J. Mientjes ◽  
Geeske M. van Woerden ◽  
Ype Elgersma
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Brain Development ◽  
Mouse Brain ◽  
Angelman Syndrome ◽  
Neurodevelopmental Disorder ◽  
Brain Regions ◽  
Critical Function ◽  
Behavioral Phenotypes ◽  
Mouse Brain Development

Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. Methods Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. Results We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. Limitations Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. Conclusions Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21.

scholarly journals Antibiotics increase aggression behavior and aggression-related pheromones and receptors in Drosophila melanogaster

2020 ◽  
Author(s):  
Michal Grinberg ◽  
Hadar Neuman ◽  
Oren Ziv ◽  
Sondra Turjeman ◽  
Rita Nosenko ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Social Behavior ◽  
Gut Microbiota ◽  
Aggressive Behavior ◽  
Social Interactions ◽  
Bacterial Species ◽  
Environmental Cues ◽  
Aggressive Behaviors ◽  
Aggression Behavior

AbstractAggression is a behavior common in most species; it is controlled by internal and external drivers, including hormones, environmental cues, and social interactions, and underlying pathways are understood in a broad range of species. To date, though, effects of gut microbiota on aggression in the context of gut-brain communication and social behavior have not been elucidated. We examine how manipulation of Drosophila melanogaster microbiota affect aggression as well as the pathways that underly the behavior in this species. Flies treated with antibiotics exhibited significantly more aggressive behaviors. Furthermore, they had higher levels of vCA and (Z)-9 Tricosene, pheromones associated with aggression in flies, as well as higher expression of the relevant pheromone receptors and transporters OR67d, OR83b, GR32a, and LUSH. These findings suggest that aggressive behavior is, at least in part, mediated by bacterial species in flies.

scholarly journals Social Isolation Alters Social and Mating Behavior in the R451C Neuroligin Mouse Model of Autism

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
E. L. Burrows ◽  
A. F. Eastwood ◽  
C. May ◽  
S. C. Kolbe ◽  
T. Hill ◽  
...  
Keyword(s):  
Social Interaction ◽  
Aggressive Behavior ◽  
Social Interactions ◽  
Mating Behavior ◽  
Social Isolation ◽  
Social Communication ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Neural Mechanisms

Autism spectrum disorder (ASD) is a neurodevelopmental disorder typified by impaired social communication and restrictive and repetitive behaviors. Mice serve as an ideal candidate organism for studying the neural mechanisms that subserve these symptoms. The Neuroligin-3 (NL3) mouse, expressing a R451C mutation discovered in two Swedish brothers with ASD, exhibits impaired social interactions and heightened aggressive behavior towards male mice. Social interactions with female mice have not been characterized and in the present study were assessed in maleNL3R451Cand WT mice. Mice were housed in social and isolation conditions to test for isolation-induced increases in social interaction. Tests were repeated to investigate potential differences in interaction in naïve and experienced mice. We identified heightened interest in mating and atypical aggressive behavior inNL3R451Cmice.NL3R451Cmice exhibited normal social interaction with WT females, indicating that abnormal aggressive behavior towards females is not due to altered motivation to engage. Social isolation rearing heightened interest in social behavior in all mice. Isolation housing selectively modulated the response to female pheromones inNL3R451Cmice. This study is the first to show altered mating behavior in theNL3R451Cmouse and has provided new insights into the aggressive phenotype in this model.

scholarly journals The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Patricia Bermudez-Martin ◽  
Jérôme A. J. Becker ◽  
Nicolas Caramello ◽  
Sebastian P. Fernandez ◽  
Renan Costa-Campos ◽  
...  
Keyword(s):  
Social Behavior ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Neurons ◽  
Therapeutic Interventions ◽  
Microbiota Composition ◽  
Microbial Metabolite ◽  
Central Dopamine Neurons ◽  
Induced Changes

Abstract Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Results Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

scholarly journals Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Lichtman ◽  
Eyal Bergmann ◽  
Alexandra Kavushansky ◽  
Nadav Cohen ◽  
Nina S. Levy ◽  
...  
Keyword(s):  
Social Behavior ◽  
Functional Connectivity ◽  
Mouse Model ◽  
Ampa Receptor ◽  
Social Preference ◽  
Autism Spectrum ◽  
Receptor Trafficking ◽  
Anterior Cingulate ◽  
The Impact ◽  
Ampa Receptor Trafficking

AbstractIQSEC2 is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure–function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome

2009 ◽  
Vol 220 (2) ◽  
pp. 341-348 ◽  
Author(s):  
Sandrine Mardirossian ◽  
Claire Rampon ◽  
Denise Salvert ◽  
Patrice Fort ◽  
Nicole Sarda
Keyword(s):  
Mouse Model ◽  
Angelman Syndrome ◽  
Deficient Mouse ◽  
Hippocampal Plasticity

Electrical Emissions in Gymnotus Carapo and Their Relation To Social Behavior

Behaviour ◽  
1970 ◽  
Vol 37 (1-2) ◽  
pp. 1-14 ◽  
Author(s):  
J.A. Valone
Keyword(s):  
Life History ◽  
Social Interaction ◽  
Social Behavior ◽  
Social Interactions ◽  
Physical Contact ◽  
Postural Responses ◽  
The Social ◽  
History Of ◽  
Electrical Stimuli

Abstract1. The relation between the social behavior and the electrical emissions of Gymnotus carapo is examined. 2. Members of the species Gymnotus carapo approach certain sources of electrical stimuli and, in a statistically significant number of instances, assume a stance parallel to the plane from which the stimuli originate. 3. The approach and postural responses elicited by electrical cues resemble those observed when two fish, placed in the same tank, interact socially. 4. Electrical cues therefore appear to facilitate certain social interactions in Gymnotus carapo. 5. The character of electrical emission in Gymnotus carapo appears to change as a function of certain social interaction: a. Interaction resembling aggression is accompanied by brief increases in the frequency of emission. b. The increases in frequency appear to be linked to thrusting movements. c. Fish interacting with one another appear to lock into a common frequency more often than fish that are not in physical contact with one another. d. During social interaction, one of the two fish is occasionally observed to halt emissions altogether. 6. The exact significance of the social behavior observed in the context of the life history of Gymnotus carapo is unknown.

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