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

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.

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SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

10.1101/2021.01.24.427868 ◽

2021 ◽

Author(s):

Kan Yang ◽

Yuhan Shi ◽

Xiujuan Du ◽

Yuefang Zhang ◽

Shifang Shan ◽

...

Keyword(s):

Social Interaction ◽

De Novo ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Genetic Components ◽

Truncating Mutation ◽

Synaptic Functions ◽

Core Symptoms

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

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CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

Journal of Cannabis Research ◽

10.1186/s42238-021-00108-7 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Serap Bilge ◽

Barış Ekici

Keyword(s):

Autism Spectrum Disorder ◽

Social Interaction ◽

Behavioral Problems ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Average Dose ◽

The Core ◽

Core Symptoms

Abstract Introduction Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. Objective In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. Materials and methods The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. Results The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients. Conclusion Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

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Behavioural and psychological characteristics in Pitt-Hopkins syndrome: a comparison with Angelman and Cornelia de Lange syndromes

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-019-9282-0 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Alice Watkins ◽

Stacey Bissell ◽

Jo Moss ◽

Chris Oliver ◽

Jill Clayton-Smith ◽

...

Keyword(s):

Social Interaction ◽

Social Communication ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Sensory Profile ◽

Psychological Characteristics ◽

Genetic Syndrome ◽

Reciprocal Social Interaction ◽

Cornelia De Lange ◽

Challenging Behaviours

Abstract Background Pitt-Hopkins syndrome (PTHS) is a genetic neurodevelopmental disorder associated with intellectual disability. Although the genetic mechanisms underlying the disorder have been identified, description of its behavioural phenotype is in its infancy. In this study, reported behavioural and psychological characteristics of individuals with PTHS were investigated in comparison with the reported behaviour of age-matched individuals with Angelman syndrome (AS) and Cornelia de Lange syndrome (CdLS). Methods Questionnaire data were collected from parents/caregivers of individuals with PTHS (n = 24), assessing behaviours associated with autism spectrum disorder (ASD), sociability, mood, repetitive behaviour, sensory processing, challenging behaviours and overactivity and impulsivity. For most measures, data were compared to data for people with AS (n = 24) and CdLS (n = 24) individually matched by adaptive ability, age and sex. Results Individuals with PTHS evidenced significantly higher levels of difficulties with social communication and reciprocal social interaction than individuals with AS, with 21 of 22 participants with PTHS meeting criteria indicative of ASD on a screening instrument. Individuals with PTHS were reported to be less sociable with familiar and unfamiliar people than individuals with AS, but more sociable with unfamiliar people than individuals with CdLS. Data also suggested areas of atypicality in sensory experiences. Challenging behaviours were reported frequently in PTHS, with self-injury (70.8%) occurring at significantly higher rates than in AS (41.7%) and aggression (54.2%) occurring at significantly higher rates than in CdLS (25%). Individuals with PTHS also evidenced lower reported mood than individuals with AS. Conclusions Behaviours which may be characteristic of PTHS include those associated with ASD, including deficits in social communication and reciprocal social interaction. High rates of aggression and self-injurious behaviour compared to other genetic syndrome groups are of potential clinical significance and warrant further investigation. An atypical sensory profile may also be evident in PTHS. The specific aetiology of and relationships between different behavioural and psychological atypicalities in PTHS, and effective clinical management of these, present potential topics for future research.

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Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B

10.21203/rs.3.rs-17171/v1 ◽

2020 ◽

Author(s):

Nisim Perets ◽

Oded Oron ◽

Shay Herman ◽

Evan Elliott ◽

Daniel Offen

Keyword(s):

Mouse Model ◽

Social Communication ◽

Neurodevelopmental Disorder ◽

Genetic Mutation ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Mice Model ◽

Restricted Interests ◽

The Social ◽

Core Symptoms

Abstract Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with main core symptoms including deficits in social-communication abilities and repetitive behaviors/restricted interests. ASD affects 1 of 88 children worldwide and currently there is no sufficiently effective treatment that alleviates its core deficits. In our previous studies, we have shown that both MSC and MSC-exo can ameliorate core ASD-like symptoms of the BTBR multifactorial mouse model of autism. Furthermore, we have demonstrated that the MSC-exo migrate to distinct neuropathological areas in several mouse models, including the frontal cortex and cerebellum in BTBR mice. In contrast to BTBR mice, which is a multifactorial model of autism, the Shank3B KO mouse is used to study ASD which develops due to a specific genetic mutation. Here we demonstrate that intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization and reduces repetitive behaviors. We also observed an increase of GABRB1 in the prefrontal cortex. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of in this mouse model autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.

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Co-occurrence of Obsessive-Compulsive Disorder and Autism Spectrum Disorder

10.1093/med-psych/9780190052775.003.0018 ◽

2021 ◽

pp. 332-351

Author(s):

Saashi A. Bedford ◽

Michelle Hunsche ◽

Connor M. Kerns

Keyword(s):

Autism Spectrum Disorder ◽

Obsessive Compulsive Disorder ◽

Social Communication ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Communication Deficits

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and, similar to obsessive-compulsive disorder (OCD), restricted and repetitive behaviors. The restricted, repetitive patterns of behaviors and interests that are characteristic of ASD often resemble the obsessions and compulsions of OCD, which can make it difficult to distinguish or differentiate the two conditions. A common challenge in diagnosing comorbid ASD and OCD is the apparent overlap in symptoms between the two disorders. This chapter discusses the differentiation between OCD and ASD, the assessment and diagnosis of OCD within the context of ASD, and the treatment of this presentation of OCD.

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Autism Spectrum Disorders and Their Clinical Management

10.2310/psych.13008 ◽

2017 ◽

Author(s):

Ernest Pedapati ◽

Jacob Shaffer

Keyword(s):

Autism Spectrum Disorders ◽

Social Communication ◽

Developmental Disorders ◽

Neurodevelopmental Disorder ◽

Genetic Defect ◽

The United States ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Key Words Autism ◽

Spectrum Disorders

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder marked by impairments in social behavior and difficulties with repetitive and restrictive behaviors. In 2012, the prevalence of ASD in the United States was estimated to be one in 68 among children age 8 years. Although the etiology of ASD is poorly understood, many researchers have identified genetic, epigenetic, and environmental factors likely involved in the disorder. In approximately 10% of cases, a definitive association with a specific genetic defect can be identified. A diagnosis of ASD is best performed through an interdisciplinary assessment and is based on diagnostic criteria. The DSM-5 criteria on the clinical features of ASD fall into two core domains: impaired social communication and interaction and restricted, repetitive behaviors, interests, or activities. Today, although no definitive “cure” for ASD exists, state-of-the-art therapies and learning environments, along with medications, have resulted in reducing disease burden and quality of life for individuals affected by ASD. This review contains 3 figures, 2 tables, and 86 references. Key words: autism spectrum disorders, developmental disorders, language speech delay, social communication

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Involvement of the habenula in the pathophysiology of autism spectrum disorder.

10.1101/2021.04.08.21255122 ◽

2021 ◽

Author(s):

Jurgen Germann ◽

Flavia Venetucci Gouveia ◽

Helena Brentani ◽

Saashi A Bedford ◽

Stephanie Tullo ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Interactions ◽

Social Communication ◽

Sensory Integration ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Resonance Imaging ◽

Restricted Interests ◽

Adults With Asd

The habenula is a small epithalamic structure that has rich widespread connections to multiple cortical, subcortical and brainstem regions. It has been identified as the central structure modulating the reward value of social interactions, behavioral adaptation, sensory integration and circadian rhythm. Autism spectrum disorder is characterized by social communication deficits, restricted interests and repetitive behaviors, and frequently associated with altered sensory perception and mood and sleep disorders. The habenula is implicated in all these behaviors and results of preclinical studies suggest a possible involvement of the habenula in the pathophysiology of this disorder. Using anatomical magnetic resonance imaging and automated segmentation we show that the habenula is significantly enlarged in children and adults with ASD compared to age matched controls. The present study is first to provide evidence of the involvement of the Hb in the pathophysiology of ASD.

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Developmental Vitamin D Deficiency Produces Behavioral Phenotypes of Relevance to Autism in an Animal Model

Nutrients ◽

10.3390/nu11051187 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1187 ◽

Cited By ~ 9

Author(s):

Asad Ali ◽

Svetlina Vasileva ◽

Mia Langguth ◽

Suzanne Alexander ◽

Xiaoying Cui ◽

...

Keyword(s):

Vitamin D ◽

Animal Model ◽

Social Interaction ◽

Motor Development ◽

Neurodevelopmental Disorder ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Ultrasonic Vocalizations ◽

Increased Risk

Emerging evidence suggests that gestational or developmental vitamin D (DVD) deficiency is associated with an increased risk of autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by impairments in social interaction, lack of verbal and non-verbal communications, stereotyped repetitive behaviors and hyper-activities. There are several other clinical features that are commonly comorbid with ASD, including olfactory impairments, anxiety and delays in motor development. Here we investigate these features in an animal model related to ASD—the DVD-deficient rat. Compared to controls, both DVD-deficient male and female pups show altered ultrasonic vocalizations and stereotyped repetitive behavior. Further, the DVD-deficient animals had delayed motor development and impaired motor control. Adolescent DVD-deficient animals had impaired reciprocal social interaction, while as adults, these animals were hyperactive. The DVD-deficient model is associated with a range of behavioral features of interest to ASD.

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Emotion Dysregulation in Autism Spectrum Disorder

The Oxford Handbook of Emotion Dysregulation ◽

10.1093/oxfordhb/9780190689285.013.20 ◽

2018 ◽

pp. 282-298

Author(s):

Emily Neuhaus

Keyword(s):

Autism Spectrum Disorder ◽

Social Communication ◽

Educational Outcomes ◽

Emotion Dysregulation ◽

Research Priorities ◽

Theoretical Models ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder

Autism spectrum disorder (ASD) is defined by deficits in social communication and interaction, and restricted and repetitive behaviors and interests. Although current diagnostic conceptualizations of ASD do not include emotional difficulties as core deficits, the disorder is associated with emotion dysregulation across the lifespan, with considerable implications for long-term psychological, social, and educational outcomes. The overarching goal of this chapter is to integrate existing knowledge of emotion dysregulation in ASD and identify areas for further investigation. The chapter reviews the prevalence and expressions of emotion dysregulation in ASD, discusses emerging theoretical models that frame emotion dysregulation as an inherent (rather than associated) feature of ASD, presents neurobiological findings and mechanisms related to emotion dysregulation in ASD, and identifies continuing controversies and resulting research priorities.

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Aberrant aggressive behavior in a mouse model of Angelman syndrome

Scientific Reports ◽

10.1038/s41598-020-79984-7 ◽

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.

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