scholarly journals Sex-dependent role for EPHB2 in brain development and autism-associated behavior

2021 ◽  
Author(s):  
Ahlem Assali ◽  
Jennifer Y. Cho ◽  
Evgeny Tsvetkov ◽  
Abha R. Gupta ◽  
Christopher W. Cowan
Keyword(s):  
Pyramidal Neurons ◽  
De Novo ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Male Mice ◽  
Sensory Sensitivity ◽  
Hyperactivity Disorder ◽  
Specific Effects ◽  
Layer V

AbstractAutism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2+/−) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2+/− female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2+/− female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice.

scholarly journals Maternal and early postnatal immune activation produce sex-specific effects on autism-like behaviors and neuroimmune function in mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
William A. Carlezon ◽  
Woori Kim ◽  
Galen Missig ◽  
Beate C. Finger ◽  
Samantha M. Landino ◽  
...  
Keyword(s):  
Immune Activation ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Poly I:C ◽  
Inflammatory Factors ◽  
Specific Effects ◽  
Immune System Activation ◽  
Pregnant Mice ◽  
The Brain

AbstractIncreasing evidence suggests a role for inflammation in neuropsychiatric conditions including autism spectrum disorder (ASD), a neurodevelopmental syndrome with higher prevalence in males than females. Here we examined the effects of early-life immune system activation (EIA)—comprising regimens of prenatal, early postnatal, or combined (“two-hit”) immune activation—on the core behavioral features of ASD (decreased social interaction, increased repetitive behavior, and aberrant communication) in C57BL/6J mice. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C) on gestational day 12.5 to produce maternal immune activation (MIA). Some offspring also received lipopolysaccharide (LPS) on postnatal day 9 to produce postnatal immune activation (PIA). EIA produced disruptions in social behavior and increases in repetitive behaviors that were larger in males than in females. Ultrasonic vocalizations (USVs) were altered in both sexes. Molecular studies revealed that EIA also produced prominent sex-specific changes in inflammation-related gene expression in the brain. Whereas both sexes showed increases in pro-inflammatory factors, as reflected by levels of mRNA and protein, expression of anti-inflammatory factors was decreased in males but increased in females. Our findings demonstrate that EIA can produce sex-specific behavioral effects and immune responses in the brain, and identify molecular processes that may contribute to resilience in females.

scholarly journals Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Natasha Bertelsen ◽  
◽  
Isotta Landi ◽  
Richard A. I. Bethlehem ◽  
Jakob Seidlitz ◽  
...  
Keyword(s):  
Repetitive Behavior ◽  
Resting State Fmri ◽  
Neural Circuitry ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Typically Developing ◽  
Out Of Sample ◽  
Genetic Mechanisms ◽  
Social Communicative ◽  
The Eu

AbstractSocial-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.

scholarly journals Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Freddy Zhang ◽  
Benjamin Rein ◽  
Ping Zhong ◽  
Treefa Shwani ◽  
Megan Conrow-Graham ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Social Preference ◽  
Intervention Strategy ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Male Mice ◽  
Behavioral Abnormalities ◽  
Deficient Mice

AbstractAutism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of the SHANK3 gene is causally linked to ASD, so adult (3–5 months old) Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adult Shank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adult Shank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.

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

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.

scholarly journals Von Economo Neuron Pathology in Familial Dysautonomia: Quantitative Assessment and Possible Implications

2020 ◽  
Vol 79 (10) ◽  
pp. 1072-1083
Author(s):  
Sarah Jacot-Descombes ◽  
Neha Keshav ◽  
Carla Micaela Santos Brosch ◽  
Bridget Wicinski ◽  
Tahia Warda ◽  
...  
Keyword(s):  
Nervous System ◽  
Pyramidal Neurons ◽  
Repetitive Behavior ◽  
Familial Dysautonomia ◽  
Autism Spectrum ◽  
Anterior Cingulate ◽  
Emotional States ◽  
Functional Link ◽  
Von Economo Neurons ◽  
Fork Cells

Abstract Von Economo neurons (VENs) and fork cells are principally located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI). Both of these regions integrate inputs from the autonomic nervous system (ANS) and are involved in decision-making and perception of the emotional states of self and others. Familial dysautonomia (FD) is an orphan disorder characterized by autonomic dysfunction and behavioral abnormalities including repetitive behavior and emotional rigidity, which are also seen in autism spectrum disorder. To understand a possible link between the ANS and the cortical regions implicated in emotion regulation we studied VENs and fork cells in an autonomic disorder. We determined the densities of VENs, fork cells, and pyramidal neurons and the ratio of VENs and fork cells to pyramidal neurons in ACC and FI in 4 FD patient and 6 matched control brains using a stereologic approach. We identified alterations in densities of VENs and pyramidal neurons and their distributions in the ACC and FI in FD brains. These data suggest that alterations in migration and numbers of VENs may be involved in FD pathophysiology thereby supporting the notion of a functional link between VENs, the ANS and the peripheral nervous system in general.

scholarly journals Identification of a β-Arrestin 2 Mutation Related to Autism by Whole-Exome Sequencing

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yunfei Tang ◽  
Yamei Liu ◽  
Lei Tong ◽  
Shini Feng ◽  
Dongshu Du ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Developmental Stages ◽  
De Novo ◽  
Repetitive Behavior ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Potential Contribution ◽  
De Novo Mutations ◽  
Whole Exome

Autism spectrum disorder (ASD) is a complex neurological disease characterized by impaired social communication and interaction skills, rigid behavior, decreased interest, and repetitive activities. The disease has a high degree of genetic heterogeneity, and the genetic cause of ASD in many autistic individuals is currently unclear. In this study, we report a patient with ASD whose clinical features included social interaction disorder, communication disorder, and repetitive behavior. We examined the patient’s genetic variation using whole-exome sequencing technology and found new de novo mutations. After analysis and evaluation, ARRB2 was identified as a candidate gene. To study the potential contribution of the ARRB2 gene to the human brain development and function, we first evaluated the expression profile of this gene in different brain regions and developmental stages. Then, we used weighted gene coexpression network analysis to analyze the associations between ARRB2 and ASD risk genes. Additionally, the spatial conformation and stability of the ARRB2 wild type and mutant proteins were examined by simulations. Then, we further established a mouse model of ASD. The results showed abnormal ARRB2 expression in the mouse ASD model. Our study showed that ARRB2 may be a risk gene for ASD, but the contribution of de novo ARRB2 mutations to ASD is unclear. This information will provide references for the etiology of ASD and aid in the mechanism-based drug development and treatment.

scholarly journals Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome

2020 ◽  
Vol 10 (4) ◽  
pp. 239
Author(s):  
Debra L. Reisinger ◽  
Rebecca C. Shaffer ◽  
Nicole Tartaglia ◽  
Elizabeth Berry-Kravis ◽  
Craig A. Erickson
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Motor Behaviors ◽  
Sensory Motor ◽  
Adolescents And Adults ◽  
Males And Females ◽  
The Impact

Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence; however, little is known about the subtypes of RRBs in adolescents and adults. Further, literature on the RRB profile of females with FXS is limited. The present study examines the RRB profile across subtypes and specific items in both males and females with FXS while assessing for differences based on age, ASD diagnosis and the impact of IQ. Participants included 154 individuals with FXS (ages 2 to 50 years old). Results revealed a peak in RRB severity in FXS between 7–12 years for the majority of RRB subscales with the exception of Sensory-Motor behaviors peaking between 2 and 12 years before declining. Distinct RRB profiles in males and females with FXS emerged in addition to significant overlap among the item and subscale levels of RRBs across gender. Further, an added diagnosis of ASD significantly increased rates of RRBs across all subscale levels, but not necessarily across all items. Lastly, IQ did not solely account for the presence of RRBs in FXS, with Sensory-Motor behaviors being driven by comorbid ASD in males with FXS, and Restricted Interest behaviors being driven by comorbid ASD regardless of gender. These findings build on the current understanding of RRBs in FXS based on gender and comorbid ASD and lay important groundwork for the development of targeted behavioral and pharmacological treatments.

scholarly journals Translational animal models of autism and neurodevelopmental disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 293-305 ◽  
Keyword(s):  
Mouse Models ◽  
De Novo ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Restricted Interests ◽  
Homologous Genes ◽  
Biological Outcomes

Autism is a neurodevelopmental disorder whose diagnosis is based on three behavioral criteria: unusual reciprocal social interactions, deficits in communication, and stereotyped repetitive behaviors with restricted interests. A large number of de novo single gene mutations and chromosomal deletions are associated with autism spectrum disorders. Based on the strong genetic evidence, mice with targeted mutations in homologous genes have been generated as translational research tools. Mouse models of autism have revealed behavioral and biological outcomes of mutations in risk genes. The field is now poised to employ the most robust phenotypes in the most replicable mouse models for preclinical screening of novel therapeutics.

scholarly journals Genome Wide Variant Analysis of Simplex Autism Families with an Integrative Clinical-Bioinformatics Pipeline

2015 ◽  
Author(s):  
Laura T Jiménez-Barrón ◽  
Jason A O'Rawe ◽  
Yiyang Wu ◽  
Margaret Yoon ◽  
Han Fang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Whole Genome ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Bioinformatics Tools ◽  
Genome Wide

Autism spectrum disorders (ASD) are a group of developmental disabilities that affect social interaction, communication and are characterized by repetitive behaviors. There is now a large body of evidence that suggests a complex role of genetics in ASD, in which many different loci are involved. Although many current population scale genomic studies have been demonstrably fruitful, these studies generally focus on analyzing a limited part of the genome or use a limited set of bioinformatics tools. These limitations preclude the analysis of genome-wide perturbations that may contribute to the development and severity of ASD-related phenotypes. To overcome these limitations, we have developed and utilized an integrative clinical and bioinformatics pipeline for generating a more complete and reliable set of genomic variants for downstream analyses. Our study focuses on the analysis of three simplex autism families consisting of one affected child, unaffected parents, and one unaffected sibling. All members were clinically evaluated and widely phenotyped. Genotyping arrays and whole genome sequencing were performed on each member, and the resulting sequencing data were analyzed using a variety of available bioinformatics tools. We searched for rare variants of putative functional impact that were found to be segregating according to de-novo, autosomal recessive, x-linked, mitochondrial and compound heterozygote transmission models. The resulting candidate variants included three small heterozygous CNVs, a rare heterozygous de novo nonsense mutation in MYBBP1A located within exon 1, and a novel de novo missense variant in LAMB3. Our work demonstrates how more comprehensive analyses that include rich clinical data and whole genome sequencing data can generate reliable results for use in downstream investigations. We are moving to implement our framework for the analysis and study of larger cohorts of families, where statistical rigor can accompany genetic findings.

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