The valproic acid-induced rodent model of autism

Behavioral and transcriptomic effects of a novel cannabinoid on a rat valproic acid model of autism.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is characterized by impairments in social communication and interaction and by the presence of restricted and repetitive patterns of behaviors, interests, or activities (American Psychiatric Association, 2013). The impairments in social communication and interaction result in limited socio-emotional reciprocity, ranging from not being able to initiate contact to initiating or responding to social contact in a way that is deviant and that may be inappropriate. Other impairments concern non-verbal communication (for example initiating and maintaining eye contact) and developing, maintaining, and understanding relationships (for example engaging in reciprocal conversations, emotion recognition, empathy, joint attention, and recognition of social cues; American Psychiatric Association, 2013).

Autism spectrum disorder (autism) is a neurodevelopmental condition characterised by impairments in social communication and interaction, plus restricted, repetitive patterns of behaviour and interests. Whilst some people embrace autism as part of their identity, others struggle with their difficulties, and some seek treatment. There are no current interventions that result in complete reduction of autism features. Acetylcholine is a neurotransmitter for the cholinergic system and has a role in attention, novelty seeking, and memory. Low levels of acetylcholine have been investigated as a potential contributor to autism symptomatology. Donepezil, galantamine, and rivastigmine (commonly referred to as acetylcholinesterase inhibitors) all inhibit acetylcholinesterase, and have slightly different modes of action and biological availability, so their effectiveness and side-effect profiles may vary. The effect of various acetylcholinesterase inhibitor on core autism features across the lifespan, and possible adverse effects, have not been thoroughly investigated. To evaluate the efficacy and harms of acetylcholinesterase inhibitors for people with the core features (social interaction, communication, and restrictive and repetitive behaviours) of autism. To assess the effects of acetylcholinesterase inhibitors on non-core features of autism. In November 2022, we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the reference lists of included studies and relevant reviews, and contacted authors of relevant studies. Randomised controlled trials (RCTs), comparing acetylcholinesterase inhibitors (e.g. galantamine, donepezil, or rivastigmine) of varying doses, delivered orally or via transdermal patch, either as monotherapy or adjunct therapy, with placebo. People of any age, with a clinical diagnosis of autism were eligible for inclusion. We used standard methodological procedures expected by Cochrane. Our primary outcomes were core features of autism and adverse effects. Secondary outcomes were language, irritability, hyperactivity, and general health and function. We used GRADE to assess certainty of evidence. We included two RCTs (74 participants). One study was conducted in Iran, the second in the USA, although exact location in the USA is unclear. Galantamine plus risperidone versus placebo plus risperidone One study compared the effects of galantamine plus risperidone to placebo plus risperidone (40 participants, aged 4 years to 12 years). Primary and secondary outcomes of interest were measured postintervention, using subscales of the Aberrant Behavior Checklist (score 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed there was little to no difference between the two groups postintervention for social communication (mean difference (MD) -2.75, 95% confidence interval (CI) -5.88 to 0.38), and restricted and repetitive behaviour (MD -0.55, 95% CI -3.47 to 2.37). Overall autism features were not assessed. Adverse events may be higher in the galantamine plus risperidone group (75%) compared with the placebo plus risperidone group (35%): odds ratio 5.57, 95% CI 1.42 to 21.86, low-certainty evidence. No serious adverse events were reported. Low-certainty evidence showed a small difference in irritability (MD -3.50, 95% CI -6.39 to -0.61), with the galantamine plus risperidone group showing a greater decline on the irritability subscale than the placebo group postintervention. There was no evidence of a difference between the groups in hyperactivity postintervention (MD -5.20, 95% CI -10.51 to 0.11). General health and function were not assessed. Donepezil versus placebo One study compared donepezil to placebo (34 participants aged 8 years to 17 years). Primary outcomes of interest were measured postintervention, using subscales of the Modified Version of The Real Life Rating Scale (scored 0 to 3; higher scores = greater impairment). Very low-certainty evidence showed no evidence of group differences immediately postintervention in overall autism features (MD 0.07, 95% CI -0.19 to 0.33), or in the autism symptom domains of social communication (MD -0.02, 95% CI -0.34 to 0.30), and restricted and repetitive behaviours (MD 0.04, 95% CI -0.27 to 0.35). Significant adverse events leading to study withdrawal in at least one participant was implied in the data analysis section, but not explicitly reported. The evidence is very uncertain about the effect of donepezil, compared to placebo, on the secondary outcomes of interest, including irritability (MD 1.08, 95% CI -0.41 to 2.57), hyperactivity (MD 2.60, 95% CI 0.50 to 4.70), and general health and function (MD 0.03, 95% CI -0.48 to 0.54) postintervention. Across all analyses within this comparison, we judged the evidence to be very low-certainty due to high risk of bias, and very serious imprecision (results based on one small study with wide confidence intervals). The study narratively reported adverse events for the study as a whole, rather than by treatment group. Evidence about the effectiveness of acetylcholinesterase inhibitors as a medication to improve outcomes for autistic adults is lacking, and for autistic children is very uncertain. There is a need for more evidence of improvement in outcomes of relevance to clinical care, autistic people, and their families. There are a number of ongoing studies involving acetylcholinesterase inhibitors, and future updates of this review may add to the current evidence.

Autism spectrum disorder is defined as a childhood onset, lifelong disorder that impacts socio-communicative development and is also characterized by rigidity and ritualistic/ repetitive patterns of behaviour. A poor long-term outcome has been demonstrated in both low-functioning autism spectrum disorder (such that patients with autism spectrum disorder and a co-existing intellectual disability) and high functioning autism spectrum disorder (such that patients with autism spectrum disorder and intellectual capability in the average or above range). There are three core features of autism spectrum disorder; which are severe and pervasive deficits in social communication and interactions; and presence of restricted, repetitive patterns of behaviour, interests, and activities and poorly developed social skills. The common clinical manifestations of autism spectrum disorders are listed below as follows; impairments in social communication and interaction (inspecting with toys rather than playing with family and playing alone), sensory anomalies (heightened sensitivity and sensory aversion), disturbed movement abilities (flapping hands or repetitive gestures).

Autism occurs in approximately 1% of children and young people,1 though the diagnosis is made less commonly in girls2 and anyone with severe intellectual disability.1 It is one of the...

Is My Son Autistic?

Wpływ otyłości u matki w czasie ciąży na ryzyko rozwoju autyzmu u dziecka

Objective. Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction and communication, restrictive and repetitive patterns of behavior, interests and activities. The aim of this study was to determine the postnatal levels of thyroid hor-mones and investigate their association with the severity of ASD symptoms. Methods. The study included 56 children (46 boys and 10 girls) with ASD aged 24-42 months. For ASD diagnostics the Autism Diagnostic Observation Schedule - second version (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) - interview with the child's parents or guard-ians were used. Venous blood was drawn right after the diagnostic procedures to analyze serum thyroid-stimulating hormone (s-TSH), free triiodothyronine (s-fT3), and free thyroxine (s-fT4) levels. Linear regression analysis was conducted to assess the relationship between the concentra-tions of thyroid hormones and ASD symptoms severity. Results. Serum concentrations of measured hormones were within normal reference ranges in almost all children. Decline of s-TSH was significantly associated with an increase in the severity of impaired social interaction and impaired communication as rated by parents (ADI-R) and with a higher prevalence of stereotyped behavior as observed in the diagnostic examination (ADOS-2). A decrease in s-fT3 was associated with higher frequency of stereotyped behavior as assessed by parents (ADI-R). Neither sex nor age were significant predictors. Conclusion. Although thyroid hormone levels were normal, we demonstrated an association of thyroid hormones with ASD symptoms.

Background In the Diagnostic and Statistical Manual and Mental Disorders, Fifth Edition (DSM-5), autism spectrum disorder (ASD) and social (pragmatic) communication disorder (SCD) were described as a new category of psychiatry nosography. SCD involves impairments in social communication and social interaction but not restricted, repetitive patterns of behavior, interests, or activities. The autism spectrum quotient (AQ) was developed to screen for autism tendencies in adults with normal intelligence. However, AQ cutoff scores for screening ASD and SCD in the DSM-5 have not been established. This study examined whether the Japanese version of the AQ (AQ-J) total scores could discriminate between an ASD group, an SCD group, and a neurotypical (NT) group. Methods Participants were 127 ASD patients, 52 SCD patients, and 49 NT individuals. Receiver operating characteristic (ROC) analyses were used to examine AQ-J total score cutoff values to distinguish between ASD and NT groups, SCD and NT groups, and ASD and SCD groups. Results In the ROC analysis for the ASD and NT groups, the area under the curve (AUC) was 0.96, and the optimum cutoff value was 23 points (sensitivity 92.9%, specificity 85.7%). The AUC for the SCD and NT groups was 0.89, and the optimum cutoff value was 22 points (sensitivity 84.6%, specificity 85.7%). The AUC for the ASD and SCD groups was 0.75; the optimum cutoff value was 32 points (sensitivity 67.7%, specificity 71.2%). Conclusion Our findings suggest the usefulness of the AQ-J in screening for ASD and SCD.

Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction associated with repetitive or stereotyped behaviour. Prenatal valproic acid (VPA) exposure in rodents is a commonly used model of ASD. Resveratrol (RSV) has been shown to prevent interneuronal and behavioural impairments in the VPA model. We investigated the effects of prenatal VPA exposure and RSV on the GABAergic synaptic transmission, brain oscillations and on the genic expression of interneuron-associated transcription factor LHX6 in the primary somatosensory area (PSSA). Prenatal VPA exposure decreased the sIPSC and mIPSC frequencies and the sIPSC decay kinetics onto layers 4/5 pyramidal cells of PSSA. About 40% of VPA animals exhibited absence-like spike-wave discharge (SWD) events associated with behaviour arrest and increased power spectrum density of delta, beta and gamma cortical oscillations. VPA animals had reduced LHX6 expression in PSSA, but VPA animals treated with RSV had no changes on synaptic inhibition or LHX6 expression in the PSSA. SWD events associated with behaviour arrest and the abnormal increment of cortical oscillations were also absent in VPA animals treated with RSV. These findings provide new venues to investigate the role of both RSV and VPA in the pathophysiology of ASD and highlight the VPA animal model as an interesting tool to investigate pathways related to the aetiology and possible future therapies to this neuropsychiatric disorder.

Answers to Your DSM-5 Questions

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.

Background: Autism is a developmental disorder characterized by troubles with social interaction and communication, and by restricted and repetitive behavior. Autism is caused by a combination of genetic and environmental factors. Risk factors include certain infections during pregnancy such as rubella as well as valproic acid, alcohol, or cocaine use during pregnancy. The controversy surrounding other proposed environmental causes, such as a certain vaccine, has been disproven. This study aimed to determine the biopsychosocial and environmental determinants of autism in children under five in Tangerang, Banten. Subjects and Method: This was an analytic observational with a cross-sectional design. This study was conducted at several special schools for children with special need children in Tangerang, Banten. A sample of 200 children under five, consisting 50 children with autism and 150 children without autism was selected for this study by fixed disease sampling. The dependent variable was the incidence of autism. The independent variables were maternal age, stress in the gestation period, maternal education, family income (with under or over Minimum Wage Limit/ MWL), and exposure to chemicals. The data on autism was collected by M-CHAT questionnaire. Stress during pregnancy was measure by Depression Anxiety Stress Scale (DASS). Other data were taken from mother and child logbook. The data were analyzed by logistic regression analysis in Stata 13. Results: The risk of autism in children under five increase with maternal age ≥ 35 years (b= 4.60; 95% CI= 1.03 – 20.55; p<0.046), stress in gestational period (b= 9.88; 95% CI= 2.19 to 44.65; p< 0.003), exposure to chemical (b= 11.85; 95% CI= 2.73 to 51.38; p<0.001). The risk of autism decrease with family income ≥ MWL (b= 0.06; 95% CI= 0.15 to 0.26; p<0.001), and maternal education ≥ high school (b= 0.15; 95% CI= 0.003 to 0.076; p<0.001). Conclusion: The risk of autism in children under five increases with maternal age ≥35 years, stress in gestational age, and exposure to chemical, but decreases with high family income and high maternal education. Keywords: autism, biopsychosocial factor, environmental factor

Early Signs

Language, Theory of Mind and Cognitive skills in Arabic-speaking children with and without autism: Evidence from network and cluster analyses