Male Autism Spectrum Disorder Research Articles

Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats

BackgroundDeletion or mutations of SHANK3 lead to Phelan–McDermid syndrome and monogenic forms of autism spectrum disorder (ASD). SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered morphology of dendrites and spines in the hippocampus, cerebellum, and striatum have been associated with behavioral impairments in Shank3-deficient animal models. Given the attentional deficit in these animals, our study explored whether deficiency of Shank3 in a rat model alters neuron morphology and synaptic ultrastructure in the medial prefrontal cortex (mPFC).MethodsWe assessed dendrite and spine morphology and spine density in mPFC layer III neurons in Shank3-homozygous knockout (Shank3-KO), heterozygous (Shank3-Het), and wild-type (WT) rats. We used electron microscopy to determine the density of asymmetric synapses in mPFC layer III excitatory neurons in these rats. We measured postsynaptic density (PSD) length, PSD area, and head diameter (HD) of spines at these synapses.ResultsBasal dendritic morphology was similar among the three genotypes. Spine density and morphology were comparable, but more thin and mushroom spines had larger head volumes in Shank3-Het compared to WT and Shank3-KO. All three groups had comparable synapse density and PSD length. Spine HD of total and non-perforated synapses in Shank3-Het rats, but not Shank3-KO rats, was significantly larger than in WT rats. The total and non-perforated PSD area was significantly larger in Shank3-Het rats compared to Shank3-KO rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the mPFC of rats that lack one copy of Shank3 and mimic the heterozygous loss of SHANK3 in Phelan–McDermid syndrome.LimitationsThe Shank3 deletion in the rat model we used does not affect all isoforms of the protein and would only model the effect of mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, the ultrastructural study focused only on synaptic structure in male Shank3-deficient rats.ConclusionsWe observed increased HD and PSD area in Shank3-Het rats. These observations suggest the occurrence of altered synaptic ultrastructure in this animal model, further pointing to a key role of defective expression of the Shank3 protein in ASD and Phelan–McDermid syndrome.

Pubertal Timing During Early Adolescence: Advanced Pubertal Onset in Females with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is characterized by impaired social communication and poor adaptation to change; thus, the onset of puberty may be a pivotal transition. This cross-sectional study measured pubertal timing to examine hypothesized differences for sex (female vs. male) and group (ASD vs. typical development [TD]). Participants included 239 children (137 ASD, 102 TD) between 10 and 13 years. The ASD group included 35 females and 102 males; the TDs included 44 females and 58 males. Pubertal onset measured by genital or pubic stage was investigated with linear regression using main effects of sex and age-by-sex interactions in TD and ASD groups and main effects of diagnosis and diagnosis-by-age interactions in males and females, controlling for body mass index, socioeconomic status, and race. In TD, examination of main effects for genital (penis/breast) stage showed no difference for male and female children (t = 1.33, P = 0.187, rdf = 92); however, there were significant differences in ASD (t = 2.70, P = 0.008, rdf = 121). For diagnosis modeled separately by sex, there was significantly earlier pubertal development in females with ASD (t = 1.97, P = 0.053, rdf = 70, but not males (t = 1.329, P = 0.186, rdf = 143). In addition, analysis of menses revealed females with ASD had significantly earlier onset than TD (t = -2.56, P = 0.018, rdf = 21). Examination of pubic stage revealed expected sex differences for TD (t = 2,674, P = 0.009, rdf = 91) and ASD (t = 3.482, P = 0.001, rdf = 121). Females with ASD evidence advanced pubertal onset relative to ASD males and TD females. Findings underscore the need for enhanced understanding of pubertal development in ASD, as differences may have significant psychological, social, physiological, and developmental consequences. LAY SUMMARY: Children with autism spectrum disorder (ASD) have difficulty with social communication and respond poorly to change, which may include the onset and course of puberty. The study measured the timing of puberty in 239 children (137 ASD and 102 typical development [TD]) between 10 and 13 years based on pubertal stage of genital (breast/penis) and pubic hair development. Females with ASD evidence advanced pubertal onset relative to ASD males and TD females. Findings underscore the need for an enhanced understanding of pubertal development in ASD.

An Exploration of Physical and Phenotypic Characteristics of Bangladeshi Children with Autism Spectrum Disorder.

This study explored the physical and clinical phenotype of Bangladeshi children with autism spectrum disorder (ASD). A totally of 283 children who were referred for screening and administered Module 1 of the Autism Diagnostic Observation Schedule (ADOS) were included. Overall, 209 met the ADOS algorithmic cutoff for ASD. A trend for greater weight and head circumference was observed in children with ASD versus non-ASD. Head circumference was significantly (p < 0.03) larger in ASD males compared with non-ASD males. A trend was also observed for symptom severity, higher in females than males (p = 0.068), with further analyses demonstrating that social reciprocity (p < 0.014) and functional play (p < 0.03) were significantly more impaired in ASD females than males. The findings help understand sex differences in ASD.

Association Between Sleep Deficiencies with Behavioral Problems in Autism Spectrum Disorder: Subtle Sex Differences.

Sleep problems are prevalent in people with autism spectrum disorder (ASD). Several studies have shown an association between sleep problems and severity of ASD-related behaviors. Most of these studies have not addressed potential sex differences either in the prevalence of the sleep problems or in their association with the manifestation of other behavioral issues in ASD. Given the strong prevalence of ASD in males, we thought it important to address whether sex differences exist in this realm. We examined the association of sleep problems with the severity of ASD-behavioral measures in a large data set collected from an online phenotyping project: Simons Foundation Powering Autism Research for Knowledge. We confirmed a high prevalence of sleep problems in ASD and a strong association between sleep problems and severity of other ASD-related behaviors. Furthermore, we were able to detect sex differences in these associations. In children with ASD, there was a slightly stronger association between repetitive behaviors and diagnosed sleep problems in females compared to males. In children without diagnosed ASD (undiagnosed siblings), there was a stronger association between sleep problems and impairments in social communication in males compared to females. These data highlight potential sex differences in the association of sleep problems and behavioral problems in ASD. LAY SUMMARY: We tested for sex differences in the association between sleep deficiencies and behavior in autism spectrum disorder (ASD). In children with ASD, we found the association between sleep problems and repetitive behaviors was slightly stronger in females. In siblings without diagnosed ASD, the association between sleep problems and social communication scores was stronger in males. These data suggest that sex might play a role in an association between sleep deficiencies and behavioral impairments.

Lifetime and Momentary Psychotic Experiences in Adult Males and Females With an Autism Spectrum Disorder.

BackgroundExisting research shows that adults with an autism spectrum disorder (ASD) are more vulnerable to develop overt psychosis. However, studies investigating (subclinical) psychotic experiences (PE) in ASD are scarce, and it is unknown if PE are accompanied with more distress in adults with ASD compared to the general population. This study examined lifetime PE and accompanying distress, momentary PE levels, and the impact of daily life stress and negative affect (NA) on momentary PE in males and females with ASD compared to controls.MethodsIn 50 adults with ASD (males N= 26, females N= 24) and 51 adults without ASD (males N= 26, females N= 25), the Community Assessment of Psychic Experiences (CAPE) was used to analyze group differences in frequency and distress of lifetime subclinical positive, negative, and depressive symptoms. The Experience Sampling Method (ESM) was used to measure momentary PE, NA, and stress (activity-related, event-related, and social stress) for 10 days. Multilevel analyses were conducted to test whether stress and NA were associated with momentary PE and whether these associations were modified by group or sex.ResultsAdults with ASD reported more lifetime CAPE negative and depressive symptoms, but similar levels of PE, than controls. Higher levels of accompanying distress were found in participants with ASD for each subscale. With respect to ESM momentary PE, higher levels were reported by adults with ASD and a stronger association between event-related stress and momentary PE was found compared to controls. This was not the case for NA, activity-related, and social stress. Overall, no significant differences between male and female outcomes were found.ConclusionAdults with ASD are more prone to encounter lifetime subclinical negative and depressive symptoms and accompanying distress compared to adults without ASD. Similar levels of lifetime PE in both groups were still accompanied with more distress in the ASD group. Furthermore, higher levels of ESM momentary PE were found in participants with ASD. Additionally, event-related stress may act as a risk factor for PE in both females and males with ASD, with a stronger risk-increasing effect than in their control counterparts.

Seeing and communicating: photography and young male adults with Autism Spectrum Disorder

Digital photography is deeply embedded in people’s daily lives, as camera phones and digital compact cameras are widely used in social and cultural settings. People have an increased agency and choice over what they want to photograph, where and when; many people carry their smartphones everywhere and share their images instantly via social media platforms. Within the recent scholarship on everyday photography, however, little attention has been paid to the photographic practices of people with Autism Spectrum Disorder (ASD), one of many marginalized groups whose photography has not been explored. This article addresses this shortfall. Drawing on a qualitative, image-based investigation, the author turns to phenomenology to examine four young male ASD adults’ unique ways of seeing and being-in-the-world as expressed through the use of their camera. Their involvement indicates that ASD people have the potential to have a powerful voice in how society conceives of what autism is and what it means to live with ASD. A case study discussion of key research findings presents examples of the pictures taken in the sphere of participants’ everyday lives, revealing that the camera acts as an extension of experience and perception, a mediator and filter. Photography enables the four male ASD individuals’ being-in-the-world and exposes the social life of this marginalized group. The article offers a significant contribution to the field of visual communication and sensory experience.

Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder

The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger’s Diagnostic Scale–Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water’s relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

The Role of Lead, Manganese, and Zinc in Autism Spectrum Disorders (ASDs) and Attention-Deficient Hyperactivity Disorder (ADHD): a Case-Control Study on Syrian Children Affected by the Syrian Crisis.

Autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are two developmental disorders that affect children worldwide, and are linked to both genetic and environmental factors. This study aims to investigate the levels of lead, manganese, and zinc in each of ASD, ADHD, and ASD with comorbid ADHD in Syrian children born or grown during the Syrian crisis. Lead and manganese were measured in the whole blood, and zinc was measured in the serum in 31 children with ASD, 29 children with ADHD, and 11 children with ASD with comorbid ADHD (ASD-C) compared with 30 healthy children, their ages ranged between 3 and 12years. Blood lead levels were higher in the groups of ASD-C (245.42%), ASD (47.57%), and ADHD (14.19%) compared with control. Lead levels were significantly higher in children with ASD in the age of 5 or less compared with control, and they were also higher in the male ASD compared with females (P = 0.001). Blood manganese levels were lower in the groups of ASD-C (10.35%), ADHD (9.95%, P = 0.026), and ASD (9.64%, P = 0.046). However, serum zinc levels were within the reference range in all groups of study. Lead and manganese were positively correlated with each other (P = 0.01). Lead increase and manganese decrease may associate with the incidence of ASD, ADHD, or the co-occurrence of both of them together. Further studies are needed to examine the relationship between metal levels and the co-occurrence of ASD and ADHD together.

Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome.

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.

Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity

Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated OXTR variants on reward network resting-state functional connectivity in males and females with and without ASD, and explore how genotype, sex, and diagnosis relate to heterogeneity in neuroendophenotypes. Females with ASD who carried a greater number of ASD-associated risk alleles in the OXTR gene showed greater functional connectivity between the nucleus accumbens (NAcc; hub of the reward network) and subcortical brain areas important for motor learning. Relative to males with ASD, females with ASD and higher OXTR risk-allele-dosage showed increased connectivity between the NAcc, subcortical regions, and prefrontal brain areas involved in mentalizing. This increased connectivity between NAcc and prefrontal cortex mirrored the relationship between genetic risk and brain connectivity observed in neurotypical males showing that, under increased OXTR genetic risk load, females with ASD and neurotypical males displayed increased connectivity between reward-related brain regions and prefrontal cortex. These results indicate that females with ASD differentially modulate the effects of increased genetic risk on brain connectivity relative to males with ASD, providing new insights into the neurobiological mechanisms through which the female protective effect may manifest.

Neurogenetic Profiles of Risk and Resilience in Female Autism

Understanding sex differences in brain function and genetics is critical to delineating the systems biology of autism spectrum disorder (ASD), but female ASD is understudied. We integrate imaging and genetic data in a sex-balanced sample of ASD and neurotypical youth to evaluate the hypothesis that there are female-specific pathways of ASD risk and resilience. FMRI data reveal a neurofunctional profile of female ASD characterized by motor, striatal, and frontal involvement not observed in male ASD. Further, we observe greater recruitment of salience and executive control networks among neurotypical girls versus neurotypical boys and autistic girls, suggesting neural correlates of the “Female Protective Effect.” Larger copy number variants containing gene(s) expressed in striatal cortex in autistic girls versus boys suggest a female-specific etiological role for potential impacts to this brain region. Our findings advocate caution in drawing conclusions regarding autistic girls based on male-predominant samples.

Variation in Social Anxiety and Separation Anxiety over Age in ASD and Non-ASD Young Males: Issues for Clinical Assessment and Treatment-Planning

ABSTRACT To further understand how young males with Autism Spectrum Disorder (ASD) experience anxiety, two specific forms of anxiety were examined in samples of boys with ASD and their non-ASD (NASD) peers. Self-reports on the Child and Adolescent Symptom Inventory (4th rev.) were collected from 117 ASD boys and 50 NASD boys, aged from 6 yr to 17 yr who were matched for IQ and age. Data regarding their Social Anxiety and Separation Anxiety were examined and indicated that the ASD boys had significantly elevated levels of both forms of anxiety compared to their NASD peers. When examined at two-yearly age intervals, the ASD boys continued to exhibit high levels of Social Anxiety over age but the NASD boys showed a gradual decrease in this form of anxiety with age. Although Separation Anxiety showed a gradual decrease with age in the ASD group, that result was different for four of the Separation Anxiety symptoms, thus identifying aspects of Separation Anxiety that may remain elevated despite decreases in some other aspects with age. These results have implications for assessment of anxiety in boys with ASD and for the development of treatment plans aimed at assisting them to function effectively.

Autism in Saudi Arabia, a challenge to Saudi families: a cross-sectional study

Background: Autism spectrum disorder (ASD) is a mental condition, usually presented from early childhood; it is often observed and diagnosed within the first 3 years of the child's life. This study aims to evaluate the challenges that families are facing regarding raising a child with Autism in Saudi Arabia. Methodology: An observational cross-sectional study was conducted in the eastern region of Saudi Arabia from December 2016 to February 2017 to assess the challenges faced by families of ASD children. This study involved all the families that have one or more autistic children between the ages of 1 and 12 years. The data were collected by using a self-administered questionnaire distributed electronically and in paper form among families with an autistic child with the help of autism centers. The data were analyzed by Statistical Package for the Social Sciences version 21. Results: The questionnaire consisted of 31 questions, a total of 61 families participated in this study. Regarding the diagnosis, the majority of the sample was diagnosed with Autism at an early age. The prevalence of ASD in males was found higher than females. Public awareness was still very poor. Families were spending a lot of money even though the government’s facilities were acceptable. The study found it to be challenging to raise an autistic child in the studied population, Conclusion: The study found families with autistic children were suffering from many challenges, psychologically, socially, emotionally, and financially in the Saudi population.

Association of human serotonin receptor 4 promoter methylation with autism spectrum disorder.

Human serotonin receptor 4 (HTR4) encodes a 5-HT4 receptor involved in learning, memory, depression, anxiety, and feeding behavior. The aim of this study was to investigate the association between the deoxyribonucleic acid (DNA) methylation of HTR4 promoter and autism spectrum disorder (ASD), a disease characterized by communication disorder and repetitive or restrictive behavior.Peripheral blood DNA was obtained from 61 ASD children and 66 healthy children, and the DNA methylation of HTR4 promoter was assessed by quantitative methylation-specific polymerase chain reaction. We used percentage of methylated reference (PMR) to represent DNA methylation level.Due to significant age differences between ASD cases and controls (3 [2, 5] years and 6 [5, 6] years, P = 3.34E-10), we used binary logistic regression analysis for adjustment. Our results showed that the DNA methylation levels of HTR4 promoter were significantly lower in children with ASD than in healthy children (median PMR: 66.23% vs 94.31%,P = .028, age-adjusted P = .034). In addition, the DNA methylation of HTR4 promoter was inversely associated with age in male ASD cases (total cases: r = –0.283, P = .027; male cases: r = –0.431, P = .002; female cases: r = –0.108, P = .752). Dual-luciferase reporter gene assay showed that the reporter gene expression in the strain with recombinant pGL3-promoter-HTR4 plasmid was significantly higher than that in the strain with pGL3-promoter plasmid (fold change = 2.01, P = .0065), indicating that the HTR4 promoter fragment may contain transcription factors to upregulate promoter activity.Our study suggested that hypomethylation of the HTR4 promoter is a potential biomarker for predicting the risk of male ASD.

On the Continuity Between Autistic and Schizoid Personality Disorder Trait Burden: A Prospective Study in Adolescence.

Although widely conceived as distinct conditions, higher-functioning autism spectrum disorder (ASD) and schizoid personality disorder (schizoid PD) share similar clinical symptomatology. This study explored the relationship between the two disorders by collecting extensively validated measures of autistic trait burden (Social Responsive Scale, Second Edition) and schizoid PD affectation (Diagnostic Interview for Genetic Studies) from clinically ascertained verbal males with and without autism ages 12 to 25 years (N = 72) via parent, teacher, and self-report. Although only a small minority of adolescents with ASD met full diagnostic criteria for schizoid PD, participants with ASD endorsed a continuous distribution of schizoid PD traits that reflected a pronounced pathological shift in comparison with those in the control group, with one half of ASD males experiencing three or more Diagnostic and Statistical Manual of Mental Disorders, 4th Edition schizoid PD criterion items "often" or "almost always." Results suggest significant amplification of schizoid PD trait burden in adolescents with ASD. ASD-specific interventions should be considered for patients with schizoid PD with premorbid histories of ASD.

Pitch Pattern Analysis in Speech of Children with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental condition. Atypical communication mostly occurs in tandem with ASD. We compared voice pitch of 16 Marathi children and adolescents with ASD of age of 7 to 18 with 27 Typically Developing (TD). Speech samples have been recorded and stored in .wav format with sampling frequency of 48000 Hz. For analysis we used PRAAT, a program for speech analysis, manipulation and synthesis. We divided the ASD and TD group into total 4 groups on basis of age and gender for comparison. We found that differences in voice pitch are present in these comparison groups, and male ASD group have more pitch variation than respective comparison groups. In future we look forward to include more ASD participants in study to increase the Marathi speech database for ASD.

IFNG/IFNG-AS1 expression level balance: implications for autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with different epidemiological, genetic, epigenetic, and environmental factors. Although its etiology is not fully understood, immune dysfunction is implicated in this disease. Recently, a large number of genes encoding long noncoding RNAs (lncRNAs) were discovered which act as positive or negative regulators of neighboring target genes. The lncRNA, Interferon gamma-antisense RNA (IFNG-AS1), regulates expression levels of the Interferon gamma (IFNG) gene. In the present study, we investigated expression of IFNG and IFNG-AS1 in 50 children with ASD (15 females and 35 males, mean age: 6 ± 1.4years) and 50 healthy controls (14 females and 36 males, mean age: 6 ± 1.74years) by real time PCR technique. The results showed significant up-regulation of IFNG and down-regulation of IFNG-AS1 expression in children with ASD compared to controls (Fold change = 1.5, P < 0.0001; Fold change = -0.143, P = 0.013, respectively). The IFNG expression level increase was more pronounced in male ASD children (Fold change = 1.621; p < 0.0001). Our data reveal a functional disruption in the interactive network of IFNG/IFNG-AS1 regulation, which could be a contributing factor in the chronic inflammatory aspect of ASD. Our findings can help understanding the underlying contributors to ASD pathogenesis and find novel treatment options for children with ASD.

Gene network analysis reveals a role for striatal glutamatergic receptors in dysregulated risk-assessment behavior of autism mouse models

Autism spectrum disorder (ASD) presents a wide, and often varied, behavioral phenotype. Improper assessment of risks has been reported among individuals diagnosed with ASD. Improper assessment of risks may lead to increased accidents and self-injury, also reported among individuals diagnosed with ASD. However, there is little knowledge of the molecular underpinnings of the impaired risk-assessment phenotype. In this study, we have identified impaired risk-assessment activity in multiple male ASD mouse models. By performing network-based analysis of striatal whole transcriptome data from each of these ASD models, we have identified a cluster of glutamate receptor-associated genes that correlate with the risk-assessment phenotype. Furthermore, pharmacological inhibition of striatal glutamatergic receptors was able to mimic the dysregulation in risk-assessment. Therefore, this study has identified a molecular mechanism that may underlie risk-assessment dysregulation in ASD.

Early negative affect in males and females with fragile X syndrome: implications for anxiety and autism

BackgroundFragile X syndrome (FXS) is a genetic disorder that is highly comorbid with anxiety and autism spectrum disorder (ASD). Elevated negative affect in young children has been associated with increased risk for both anxiety and ASD; however, these relations remain poorly understood in FXS.MethodsThe present prospective longitudinal study examined the trajectory of negative affect from infancy through preschool in males and females with FXS and typical development and its relation to anxiety and ASD.ResultsResults indicate a complex association reflecting group, developmental, and sex effects. Specifically, the group with FXS displayed a trajectory of increasing negative affect across age that was distinct from the typical controls. This atypical trajectory of negative affect in FXS was driven by sex effects in that males showed lower negative affect during infancy followed by steep increases across the toddler and preschool years whereas the females displayed a flatter trajectory. Finally, elevated negative affect predicted anxiety symptoms in males, but not females, with no relationship to ASD in males or females with FXS.ConclusionsThe current work addresses the importance of studying the development of psychopathology in a specific neurogenetic population. Temperamental negative affect was shown to be an important early marker for anxiety in young children with FXS, with subtle differences observed between males and females.

Chronic subconvulsive activity during early postnatal life produces autistic behavior in the absence of neurotoxicity in the juvenile weanling period

The diagnosis of autism spectrum disorder (ASD) varies from very mild to severe social and cognitive impairments. We hypothesized that epigenetic subconvulsive activity in early postnatal life may contribute to the development of autistic behavior in a sex-related manner. Low doses of kainic acid (KA) (25–100 μg) were administered to rat pups for 15 days beginning on postnatal (P) day 6 to chronically elevate neuronal activity. A battery of classical and novel behavioral tests was used, and sex differences were observed. Our novel open handling test revealed that ASD males nose poked more often and ASD females climbed and escaped more frequently with age. In the social interaction test, ASD males were less social than ASD females who were more anxious in handling and elevated plus maze (EPM) tasks. To evaluate group dynamics, sibling and non-sibling control and experimental animals explored 3 different shaped novel social environments. Control pups huddled quickly and more frequently in all environments whether they socialized with littermates or non-siblings compared to ASD groups. Non-sibling ASD pups were erratic and huddled in smaller groups. In the object recognition test, only ASD males spent less time with the novel object compared to control pups. Data suggest that chronic subconvulsive activity in early postnatal life leads to an ASD phenotype in the absence of cell death. Males were more susceptible to developing asocial behaviors and cognitive pathologies, whereas females were prone to higher levels of hyperactivity and anxiety, validating our postnatal ASD model apparent in the pre-juvenile period.