Targeting synaptic plasticity and acetylcholine dysregulation in the medial prefrontal cortex: Rosmarinic acid attenuates Autism-like phenotypes in Shank3B-/- mice via the CREB/BDNF pathway.

Spironolactone Partially Reverses Autism-Like Behaviors Linked to ErbB4 and mTOR Phosphorylation in the Mouse Prefrontal Cortex and Striatum.

Special Report: Autism Spectrum Disorder and Inflexible Thinking—Affecting Patients Across the Lifespan

<p id=p00005>Autism spectrum disorder (ASD) is a neurodevelopmental disorder that originated from childhood, social deficits are core symptoms of ASD. Previous studies, from a information processing perspective, proposed that a deficit in social cognitive is the cause of social impairment. However, research showed that the lack of cognitive ability was not the only reason for the social deficits of individuals with ASD, but also closely related to the social motivation deficits. Social motivation theory suggests that social motivation deficits exist in the early life of individuals with ASD and affect their subsequent development. Studying the social motivation of individuals with ASD is of great value to explain the causes of their social deficits and find the direction of intervention in the future. Therefore, this study summarizes the specific behaviors and internal and external influencing factors of social motivation deficits in individuals with ASD. In the future, it is important to comprehensively consider these factors, to strengthen the integrated research on the social motivation theory of individuals with ASD, so as to accurately understand the social motivation deficits of individuals with ASD. <br/>Social motivation theory suggests that social motivation is a powerful driving force to guide individual’s social behavior. The theory also highlights that social behavior is mainly manifested in social orientation, social reward and social maintenance, so this paper firstly summarizes the related researches on the behavioral level of social motivation deficits in individuals with ASD, which are mainly reflected in the following three aspects: (1) The results of social orientation research show that individuals with ASD often show impaired attention to social stimuli, reduced direct gaze on the face, reduced gaze on the eyes, etc. On the one hand, this deficit is related to their abnormal face processing strategies; on the other hand, they may have difficulties in representing the intrinsic reward value of social stimuli; (2) The results of social reward research show that social reward stimulation has no significant incentive effect on individuals with ASD. They lack the ability to experience the happiness of social interaction, cant get happiness from interaction and lack the desire to help others, which is related to the abnormality of reward processing system (amygdala, ventral striatum, prefrontal cortex and other brain regions). (3) The results of social maintenance research show that individuals with ASD have few social maintenance strategies, they are not good at maintaining social relationships with others, do not actively show their own advantages, do not actively imitate others, and lack the desire and motivation to establish and maintain good relationships with others. <br/>Finally, because the research conclusions of social motivation deficits in individual with ASD are not completely consistent, this paper comprehensively and systematically analyzes the influencing factors of social motivation deficits, and finds that it includes internal factors and external factors. The internal factors are mainly reflected in individuals age, gender and physiological mechanism, while the external factors are mainly reflected in social communication environment, experimental stimulus materials, difficulty and nature of experimental tasks. In order to improve the credibility and effectiveness of the research on the social motivation of individuals with ASD, and fully and accurately grasp the characteristics of social motivation in individuals with ASD, in the future, it is important to study the social motivation deficits of individuals with ASD of different ages and genders, to optimize the experimental tasks, broaden the types of materials, further improve the experimental design, and to strengthen the integrated research on the social motivation theory of individuals with ASD, deeply explore the relationship among the behavioral, biological and evolutionary levels under this theory, and further analyze the relationship among the three behaviors of social motivation(social orientation, social reward and social maintenance).

Autism in DSM-5

Striatal Development in Autism: Repetitive Behaviors and the Reward Circuitry

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and cognitive impairments. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation/inhibition (E/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT1A receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635—a 5-HT1A receptor antagonist—antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT1A receptors in prenatal VPA mice.

Autism is a neurodevelopmental disorder characterized by dysfunction in three primary behavioural domains: repetitive behaviours, social deficits, and language abnormalities. There is evidence that abnormalities exist in the serotonin (5-HT) system in autism spectrum patients. Furthermore, 5-HT is known to play a role in repetitive and social behaviours. This study examined the effect of m-chlorophenylpiperazine (m-CPP) on repetitive behaviours and prolactin response in 11 adults with autism or Aspergers disorder and 8 age- and gender-matched healthy controls via randomized double-blind, m-CPP and placebo challenges. The primary outcome measure was an instrument rating six repetitive behaviours: need to know, repeating, ordering, need to tell/ask, self-injury, and touching. Patients with autism spectrum disorders showed a significant increase in repetitive behaviours at end-point following oral m-CPP in comparison to placebo. Additionally subjects with autism spectrum disorders showed a significantly increased prolactin response to m-CPP compared to normal controls, with neither group responding to placebo. This study provides further evidence for altered 5-HT sensitivity in individuals with autism spectrum disorders, as well as a possible relationship between repetitive behaviours in autism spectrum disorders and abnormalities in the 5-HT system.

BackgroundPotocki-Lupski syndrome (PTLS) and Smith-Magenis syndrome (SMS) are related genomic disorders, as duplication 17p11.2 (associated with PTLS) is the reciprocal recombination product of the SMS microdeletion. While SMS has a relatively well-delineated behavioural phenotype, the behavioural profile in PTLS is less well defined, despite purported associations with autism spectrum disorder (ASD) and the suggestion that some behaviours may be diametric to those seen in SMS.MethodsCaregivers of individuals with PTLS (N = 34; M age = 12.43, SD = 6.78) completed online behavioural questionnaires, including the Challenging Behaviour Questionnaire (CBQ), the Activity Questionnaire (TAQ), the Repetitive Behaviour Questionnaire (RBQ), the Mood, Interest and Pleasure Questionnaire-Short Form (MIPQ-S) and the Social Communication Questionnaire (SCQ), which assesses behaviours associated with ASD. Individuals with PTLS were matched on age and adaptive functioning to individuals with SMS (N = 31; M age = 13.61, SD = 6.85) and individuals with idiopathic ASD (N = 33; M age = 12.04, SD = 5.85) from an existing dataset.ResultsIndividuals with PTLS and SMS were less impaired than those with idiopathic ASD on the communication and reciprocal social interaction subscales of the SCQ, but neither syndrome group differed from idiopathic ASD on the restricted, repetitive and stereotyped behaviours subscale. On the repetitive behaviour measure, individuals with PTLS and idiopathic ASD scored higher than individuals with SMS on the compulsive behaviour subscale. Rates of self-injury and property destruction were significantly lower in PTLS and idiopathic ASD than in SMS. No between-syndrome differences were found in relation to overactivity or mood; however, impulsivity was greater in SMS than in PTLS.ConclusionsFindings suggest some overlap in the behavioural phenotype of PTLS and features of ASD symptomatology; however, the overall profile of behaviours in PTLS appears to be divergent from both idiopathic ASD and SMS. Relative to idiopathic ASD, PTLS is not characterised by communication or social interaction deficits. However, restricted and repetitive behaviours were evident in PTLS, and these may be characterised specifically by compulsive behaviours. While several behavioural differences were identified between PTLS and SMS, there was little evidence of diametric behavioural phenotypes, particularly in relation to social behaviour.

Big Data Approach to Characterize Restricted and Repetitive Behaviors in Autism.

Towards understanding sex differences in autism spectrum disorders

Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental disorders, characterized by social interaction deficit, stereotyped or repetitive behaviors. Apart from these core symptoms, a great number of individuals with ASD exhibit higher levels of anxiety and memory deficits. Previous studies demonstrate pronounced decrease of γ-aminobutyric acid B1 receptor (GABAB1R) protein level of frontal lobe in both ASD patients and animal models. The aim of the present study was to determine the role of GABAB1R in ASD-related behavioral aberrations. Herein, the protein and mRNA levels of GABAB1R in the prefrontal cortex (PFC) of sodium valproic acid (VPA)-induced mouse ASD model were determined by Western blot and qRT-PCR analysis, respectively. Moreover, the behavioral abnormalities in naive mice with GABAB1R knockdown mediated by recombinant adeno-associated virus (rAAV) were assessed in a comprehensive test battery consisted of social interaction, marble burying, self-grooming, open-field, Y-maze and novel object recognition tests. Furthermore, the action potential changes induced by GABAB1R deficiency were examined in neurons within the PFC of mouse. The results show that the mRNA and protein levels of GABAB1R in the PFC of prenatal VPA-induced mouse ASD model were decreased. Concomitantly, naive mice with GABAB1R knockdown exhibited ASD-like behaviors, such as impaired social interaction and communication, elevated stereotypes, anxiety and memory deficits. Patch-clamp recordings also revealed that GABAB1R knockdown provoked enhanced neuronal excitability by increasing action potential discharge frequencies. Overall, these findings support a notion that GABAB1R deficiency might contribute to ASD-like phenotypes, with the pathogenesis most likely resulting from enhanced neuronal excitability. SubheadingsGABAB1 Knockdown Induces Behavioral Aberrations with ASD

BackgroundRestricted and repetitive behaviors are defining features of autism spectrum disorder (ASD). Under revised diagnostic criteria for ASD, this behavioral domain now includes atypical responses to sensory stimuli. To date, little is known about the neural circuitry underlying these features of ASD early in life.MethodsLongitudinal diffusion tensor imaging data were collected from 217 infants at high familial risk for ASD. Forty-four of these infants were diagnosed with ASD at age 2. Targeted cortical, cerebellar, and striatal white matter pathways were defined and measured at ages 6, 12, and 24 months. Dependent variables included the Repetitive Behavior Scale-Revised and the Sensory Experiences Questionnaire.ResultsAmong children diagnosed with ASD, repetitive behaviors and sensory response patterns were strongly correlated, even when accounting for developmental level or social impairment. Longitudinal analyses indicated that the genu and cerebellar pathways were significantly associated with both repetitive behaviors and sensory responsiveness but not social deficits. At age 6 months, fractional anisotropy in the genu significantly predicted repetitive behaviors and sensory responsiveness at age 2. Cerebellar pathways significantly predicted later sensory responsiveness. Exploratory analyses suggested a possible disordinal interaction based on diagnostic status for the association between fractional anisotropy and repetitive behavior.ConclusionsOur findings suggest that restricted and repetitive behaviors contributing to a diagnosis of ASD at age 2 years are associated with structural properties of callosal and cerebellar white matter pathways measured during infancy and toddlerhood. We further identified that repetitive behaviors and unusual sensory response patterns co-occur and share common brain-behavior relationships. These results were strikingly specific given the absence of association between targeted pathways and social deficits.

Background. Clinical polymorphism and polymorphism are inherent in the clinical phenotype of children with autism spectrum disorders (ASD). There is a consensus, relatively high, between 5% and 38% of the prevalence of epilepsy in ASD. There are reasons to believe that ASD with epilepsy and specific epileptic activity on EEG and ASD with hyperkinetic symptoms without signs of epileptic process can be determined by different variants of genetic polymorphism or by different variants of gene expression, determined by different influences. Objective – to study the features of the clinical phenotype of ASD in preschool and school-age children with epileptic seizures and specific epileptic activity on EEG. Materials and methods. In the Department of Mental Disorders of Children and Adolescents of the Institute of Psychiatry of the Ministry of Health of Ukraine 116 children aged 2-10 years with ASD were examined. The study group was divided into three subgroups: subgroup A – 23 children with a history of epileptic seizures, subgroup B – 35 children with specific forms of epileptic activity on EEG without epileptic seizures, subgroup C – 19 children with ASD having specific epileptic activity for EEG repetitive involuntary movements (motor stereotypes, motor tics) and vocalizations (vocal tics). The control group consisted of 39 children with ASD non a history of seizures and specific epileptic activity on the EEG. The follow-up of children with ASD in the comparison groups was performed for 1-1.5 years. We used such research methods: clinical-psychopathological, psychodiagnostic, psychometric, statistical. Results. In children with ASD and comorbid epileptic seizures, disorders of social reciprocity are of crucial diagnostic importance. Communication disorders and recurrent, stereotyped behaviors, movements, and interests in children in this group are significantly less common than in comparison groups. Incidents of repetitive stereotypes in these children are associated with sensory impairments and autostimulations. Children with ASD, complicated by severe and frequent epileptic seizures, are characterized by impaired social reciprocity and communication against the background of regression or stagnation of speech and motor skills development. Disorders of communication and repetitive behavior in ASD in children of different ages are represented by different monoqualitative syndrome (phenotypes). Younger children less than 6 years of age are dominant in stereotypical movements, while children aged 6-8 years have repetitive behaviors associated with the overriding interests. Two subtypes of clinical phenotypes of ASD were identified: the variant with symptoms, which more closely determined the stereotypical sensor and motor behavior and the variant with symptoms of insistence on equality, with the overriding interests of preservation, identity. Movement stereotypes predominated in children with ASD without epileptic seizures and without epileptic activity on EEG. In children with ASD and epileptic activity on EEG, motor stereotypes and repetitive identity-preserving behavior were equally common. Conclusions. Disorders of social reciprocity, communication, repetitive behavior, in particular stereotyped movements are diagnostically significant signs of ASD, in particular ASD complicated by epileptic seizures, ASD with specific epileptic activity on EEG. According to the results of a long 1-1.5 years’ prospective study, it was established that the clinical phenotype of ASD with epileptic seizures, ASD without epileptic seizures with specific epileptic activity on EEG and RAS without epileptic seizures and changes in EEG are characterized by differing clinical picture and course. Qualitative communication disorders and stereotypical movements in addition to ASD are observed in other psychiatric disorders, including Tourette disorder, obsessive-compulsive disorders, and intellectual disability. Expressed repeated identity-preserving behavior is the basis for dual diagnosis of ASD and obsessive-compulsive disorder. Motor and vocal tics may be the basis for dual diagnosis of ASD and Tourette’s disorder. The presence of age-related pathoplasty of clinical manifestations of ASD in the comparison groups was established.

Restricted and repetitive behaviors (RRBs) are one of the core features of autism spectrum disorders (ASD). RRBs encompass a broad range of heterogeneous behaviors, such as repetitive and stereotyped motor behavior or speech, atypical sensory behavior, inflexible interest and rituals, and insistence on the sameness of environment. While a large amount of previous research has focused on social deficits in ASD, little attention has been paid to their RRBs. The definition, classification, and underlying mechanism of RRBs have remained to be clarified. Recently, Diagnostic and Statistical Manual of Mental Disorders (5th ed, DSM-V) has classified RRBs into several subcategories and renewed the diagnostic criteria of RRBs. New theories and evidence from neurobiological, cognitive psychological, and developmental psychological research are also emerging about the etiology of RRBs. The first aim of this review is to introduce the newest definition and subcategories of RRBs based on DSM-V. We also discuss and compare different structural models of RRBs derived from several factor analysis studies. The second aim is to summarize the current assessment tools of RRBs in autism. Besides the “golden standard” -- the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R), and several common used questionnaires such as Repetitive Behavior Scale-Revised (RBS-R) and Repetitive Behavior Questionnaire-2 (RBQ-2), new techniques including eye-tracking, accelerometry, and electrodermal activity (EDA) have been applied into the studies of RRBs. The third aim of this review is to discuss the potential causal origins underlying the RRBs. The neurobiological and cognitive mechanism of RRBs, as well as other factors that directly related to the onset of RRBs have been summarized. The neurobiological evidence indicates that the atypical activity of neurotransmitters, the imbalanced activity among the corticostriatal circuits, and the neuroanatomical alterations play important roles on the RRBs. From the perspective of cognitive psychology, classical theories such as executive functions, weak central coherence, extreme male brain theory, and operational conditioning all offer their own explanations for the onset of RRBs. Besides, the hyper- or hypo-arousal theory indicates that RRBs may function as coping strategies for the individuals with ASD to regulate levels of arousal or anxiety, with the intolerance of uncertainty as the mediator. The evidence from developmental psychology focus on the developmental trajectory of RRBs across age. Results from longitudinal studies identify the significant influence of age and intelligence on the developmental trajectory of RRBs. Severe impacts of environmental deprivation and social isolation on the RRBs have also been shown in animal and human studies and provide implication for early intervention. Finally, several future directions for the research on RRBs in ASD have also been proposed based on the current literature. We recommend future research that focuses on the united standard for classification and the direct connection between neurobiology and behavior. Also, a clear understanding of the developmental trajectories of RRBs in typical developing children and children with ASD is of importance for effective early interventions. Last but not least, the characteristics of parents and the prenatal maternal stress are worthy of future investigations.

The prevalence of autism spectrum disorder (ASD) is increasing in an epidemic-like fashion, yet no drugs are available to treat this debilitating neurodevelopmental disorder. Enhancing oxytocin (OXT) signaling may improve social functioning in ASD but has pharmacological limitations if used systemically. We, therefore, investigated the impact of a brain-penetrant melanocortin 4 receptor (MC4R) agonist that stimulates endogenous OXT release on an environmental (toxicant) ASD mouse model. C57BI/6N dams were exposed perinatally to polybrominated diphenyl ethers (PBDEs), a commercial mixture of flame retardants, DE-71 at 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d for 10 weeks. Controls received corn oil vehicle (VEH/CON). L-DE-71 females and L-DE-71 and H-DE-71 males did not prefer novel conspecifics on a social novelty preference (SNP) test, indicating deficient short-term social recognition memory. In adult offspring, treatment with MC4R agonist, Ro21-3225 trifluoroacetate salt (7.5 and 15mg/kg ip) or intranasal OXT (iOXT, 9IU/kg) reversed the deficient SNP in FMR1KO females (p&lt;0.05, n=4) but not L-DE-71 females. In adult males, both MC4R agonist and iOXT reversed deficient SNP in L-DE-71 and H-DE-71 mice (p&lt;0.05-.01, n=3-5/group). To investigate the effects of intervention during the critical period of development of the OXT system, we examined outcomes of chronic developmental administration of iOXT in offspring at postnatal day (P)28-33 on long-term social recognition memory (SRM) and repetitive behavior using the marble burying (MB) test. We also examined OXT immunoreactivity in the paraventricular nucleus of the hypothalamus (PVH) and the connectivity of the OXTergic circuit from the prefrontal cortex (PFC) to the basolateral amygdala (BLA). DE-71-exposed offspring received intranasal oxytocin (iOXT; 0.1IU/kg) or saline (iSAL) at P7-21. Compared to vehicle controls, L-DE-71 female and H-DE-71 male offspring receiving iSAL showed deficient SRM (n=3-5). iOXT prevented long-term SRM deficits in DE-71-exposed females (p&lt;0.0001, n=11) but not the exaggerated digging on MB in juvenile L-DE-71 females or males vs. vehicle controls. L-DE-71+iOXT females also displayed reduced PVH OXT immunoreactivity vs. L-DE-71+iSAL (p&lt;0.01, n=4/group). No significant effects of iOXT were observed on PFC-BLA connectivity (n=2-4/group). Our data suggests that developmental iOXT and adult activation via MC4R agonist treatment improves social but not repetitive behaviors in a sex-dependent manner, pointing to the critical role of OXT and its therapeutic potential to improve ASD-like symptoms caused by maternal transfer to offspring of environmental pollutants such as PBDEs. Funding: This work was supported by a RISE fellowship to AGC, NIH fellowship award F31ES034304 to E.V.K., and a UCR COR grant to MCC. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.