Deficits In Social Interaction Research Articles

Autism: Clinical impacts and late diagnosis in women - Literature review

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder, marked by deficits in communication and social interaction and restricted and repetitive behavior patterns. With the expansion of information dissemination about autism and improvements in diagnostic methods, the prevalence of the disorder has increased considerably in recent decades. However, because autism has multiple facets and different presentations, diagnosis is still a challenge, especially in females, where there are singularities that further undermine suspicions, leading to underdiagnosis. Given this, there are multiple questions about the causes and implications of these factors in the diagnosis of autistic girls and women. Thus, the objective of this research is to verify the causal factors and clinical implications associated with the difficulty in diagnosing ASD in females. This is a narrative bibliographic review, in which research was carried out in established databases. In general, it is noted that the diagnosis of autism in girls and women can be impacted by genetic, developmental, psychological, social and cultural influences, involving factors such as subtlety of symptoms, capacity for social adaptability, lack of studies, failure to diagnostic methodologies and instruments, as well as stereotypes and prejudices. Understanding these elements is essential to broaden the perspective of girls and women with ASD, highlight their particularities and ensure that they receive early diagnosis and treatment.

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

"Therapeutic potential of licorice extract in a prenatal valproic acid model of autism spectrum disorder in Wistar rats: Neurobehavioral and neurobiochemical insights"

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), impose significant burdens on society due to their genetic and clinical complexity. We explored the therapeutic potential of Glycyrrhiza glabra (licorice) extract in a prenatal valproic acid (VPA) model of ASD. Neurobehavioral parameters encompassing social interaction, locomotor activity, repetitive behaviour, anxiety-related behaviour, and learning and memory were assessed in Wistar rat offspring. Licorice extract administration at 150 mg/kg and 300 mg/kg was initiated from postnatal day 21, emulating the developmental stage of early childhood. The study incorporated a controlled group, a VPA-induced ASD group, and groups treated with two different doses of licorice extract and Risperidone.Results revealed that licorice extract, particularly at 300 mg/kg, exhibited remarkable potential in restoring social interaction deficits, enhancing locomotor activity, attenuating repetitive behaviour, and mitigating anxiety-related behaviour-like behaviours. Furthermore, licorice extract displayed cognitive benefits, as evidenced by the discrimination index enhancement in object recognition memory. Importantly, licorice extract demonstrated modulatory effects on neuroinflammation and oxidative stress, evident through suppressed interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels, as well as reduced thiobarbaturic acid reactive substances (TBARS) in the brain.These findings underscore the promising neuroprotective properties of Glycyrrhiza glabra extract against prenatal VPA-induced ASD-like behaviours. The elucidation of licorice's multifaceted impact on behaviour, cognition, and neurobiochemical markers offers a potential avenue for future therapeutic interventions for ASD, meriting further investigation in clinical contexts. This study contributes to the expanding knowledge of natural compounds in ameliorating complex neurodevelopmental disorders and highlights the necessity of multi-faceted approaches to address their intricate etiology and manifestation.

Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits and repetitive behaviors. A study of autistic human subjects has identified RFWD2 as a susceptibility gene for autism, and autistic patients have 3 copies of the RFWD2 gene. The role of RFWD2 as an E3 ligase in neuronal functions, and its contribution to the pathophysiology of ASD, remain unknown. We generated RFWD2 knockin mice to model the human autistic condition of high gene dosage of RFWD2. We found that heterozygous knockin (Rfwd2+/-) male mice exhibited the core symptoms of autism. Rfwd2+/- male mice showed deficits in social interaction and communication, increased repetitive and anxiety-like behavior, and spatial memory deficits, whereas Rfwd2+/- female mice showed subtle deficits in social communication and spatial memory but were normal in anxiety-like, repetitive, and social behaviors. These autistic-like behaviors in males were accompanied by a reduction in dendritic spine density and abnormal synaptic function on layer II/III pyramidal neurons in the prelimbic area of the medial prefrontal cortex (mPFC), as well as decreased expression of synaptic proteins. Impaired social behaviors in Rfwd2+/- male mice were rescued by the expression of ETV5, one of the major substrates of RFWD2, in the mPFC. These findings indicate an important role of RFWD2 in the pathogenesis of autism.

Effects of hyperbaric oxygen therapy on autistic behaviors and GRIN2B gene expression in valproic acid-exposed rats.

Autism is a complex neurodevelopmental condition characterized by deficits in social interaction, communication, and restricted repetitive behaviors. Hyperbaric oxygen therapy (HBOT) has emerged as a potential treatment for autism, although its effects on behavior and gene expression are not well understood. The GRIN2B gene, known for its involvement in encoding a glutamate receptor subunit crucial for neuron communication and associated with autism, was a focus of this study. Using a rat model induced by prenatal exposure to valproic acid, we examined the impact of HBOT on autism-like behaviors and GRIN2B gene expression. Male Wistar rats were categorized into four groups: control, VPA (valproic acid-exposed), VPA+HBOT [2 atmosphere absolute (ATA)], and VPA+HBOT (2.5 ATA). The rats underwent several behavioral tests to assess social behavior, anxiety, stereotype and exploratory behaviors, and learning. Following the behavioral tests, the HBOT groups received 15 sessions of HBOT at pressures of 2 and 2.5 (ATA), and their behaviors were re-evaluated. Subsequently, real-time PCR was employed to measure GRIN2B gene expression in the frontal lobe. Our results indicated that HBOT significantly increased social interaction and exploratory behaviors in VPA-exposed rats, alongside elevated GRIN2B gene expression in their frontal lobe. Our findings imply that HBOT might have a potential role in ameliorating autism-related behaviors in the VPA rat model of autism through potential modulation of GRIN2B gene expression. However, additional research is essential to fully comprehend the underlying mechanisms and refine the HBOT protocol for optimizing its effectiveness in improving autism-related symptoms.

Improvement of symptoms in children with autism by TOMATIS training: a cross-sectional and longitudinal study.

Autism spectrum disorder (ASD) is a neurological condition that is marked by deficits in social interaction, difficulty expressing oneself, lack of enthusiasm, and stereotypical conduct. The TOMATIS training method is an effective music therapy for children with ASD for its individually developed programs to improve behavioral deficits. The research employed both longitudinal and crosssectional designs. In the cross-sectional study, the experimental group showed significant improvement in symptoms after TOMATIS training compared to the control group of children with ASD. The results validated the effect of TOMATIS treatment for ASD-related deficits, including perceptual-motor, attentional, social, and emotional issues. ASD's auditory hypersensitivity hampers social information processing, but TOMATIS enhances cochlear frequency selectivity, aiding in capturing relevant auditory stimuli. In addition, the longitudinal study confirmed these findings, which proved TOMATIS training effective in clinically treating ASD. This study focused on audiometric indicators and behavioural improvement, elucidating the mechanisms behind the training's success. Behavioral improvements might stem from TOMATIS' frequency selectivity, reshaping auditory organ-cortical feedback loops to filter interference and focus on valid information.

Systemic histone deacetylase inhibition ameliorates the aberrant responses to acute stress in socially isolated male mice.

Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity that can precipitate stress-related psychiatric disorders. We found that male mice after 8weeks of adolescent social isolation (SI) have markedly increased aggression after being exposed to 2h of restraint stress (RS), which was accompanied by a significant increase of AMPA receptor- and NMDA receptor-mediated synaptic transmission in prefrontal cortex (PFC) pyramidal neurons of SIRS males. Compared to group-housed counterparts, SIRS males exhibited a significantly decreased level of histone H3 acetylation in PFC. Systemic administration of class I histone deacetylase inhibitors, romidepsin or MS-275, ameliorated the aggressive behaviour, as well as general social interaction deficits, of SIRS males. Electrophysiological recordings also found normalization of PFC glutamatergic currents by romidepsin treatment of SIRS male mice. These results revealed an epigenetic mechanism and intervention avenue for aggression induced by chronic social isolation. KEY POINTS: Adolescent chronic social isolation can precipitate stress-related psychiatric disorders. A significant increase of glutamatergic transmission is found in the prefrontal cortex (PFC) of socially isolated male mice exposed to an acute stress (SIRS ). Treatment with class I histone deacetylase (HDAC) inhibitors ameliorates the aggressive behaviour and social interaction deficits of SIRS males, and normalizes glutamatergic currents in PFC neurons. It provides an epigenetic mechanism and intervention avenue for aberrant stress responses induced by chronic social isolation.

The development of social-conversational skills in children with autism spectrum disorder: similarities and differences with typically developing children and late talkers. Pilot study.

Many studies have emphasized the importance of the development of pragmatic skills in young children. Pragmatic deficits, reflected in poor conversational skills, are considered the hallmark of language impairment in Autism Spectrum Disorder (ASD). Our study has compared the assertive and responsive skills of a group of 600 typically developing children, 83 late talkers (LT) and 29 children with ASD (of which 24 boys and 5 girls) aged between 27 and 60 months using the questionnaires the "Child's First Vocabulary- Gestures, Words and Phrases"- PVB and "The Child's Socio-Conversational Skills"- ASCB. The analysis of the results showed that the socio-conversational abilities of children with autism improve with increasing age, that the gap in these abilities between children with typical development and those with ASD is very wide and the differences between the two samples are statistically significant. Moreover, the percentage of LTs with immature assertive and responsive skills is lower than the percentage of autistic children; in fact, despite difficulties in lexical and morphosyntactic development, the absence of deficits in social interaction allows LTs to perform better.

The Autism Spectrum Disorder and Its Possible Origins in Pregnancy.

Autism Spectrum Disorder (ASD) belongs to the group of neurodevelopmental disorders, and has a high prevalence, affecting 1 in 100 children according to data from the World Health Organization (WHO). To be diagnosed with ASD, the child must have persistent deficits in communication and social interactions, and restricted and repetitive patterns of behavior, interests, or activities. Despite its prevalence, the etiology of ASD is still uncertain, with multifactorial characteristics, including those associated with the gestational period, where maternal exposure to biological, chemical, or physical hazards occurs, some of which have already been proposed as causes of ASD outcomes. Since pregnancy requires a balance between the maternal-fetal binomial, the breakdown of this balance caused by such environmental hazards can lead to altered fetal neurodevelopment, including ASD. With this firmly in mind, this review aims to compile the most recent data on the gestational causes that may be associated with the development of ASD to help health professionals identify risk factors and act for the prevention and management of ASD.

Critical period of exposure to mercury and the diagnostic of autism spectrum disorder: A systematic review.

Autism spectrum disorder (ASD) is characterized by repetitive behaviors and deficits in social interaction. Its etiology is not completely clear, but both genetic and environmental factors contribute to and influence its development and course. The increased number of autism cases in recent years has been strongly associated with increased exposure to heavy metals. Mercury (Hg) has gained prominence in the scientific literature as a result of its presence as an urban pollutant and well-described neurotoxicity. This review assessed the relationship between Hg exposure in the pre- and post-natal period and ASD. The systematic review identified observational clinical studies and pre-clinical trials in journals indexed in the PubMed, Embase, ProQuest, and LILACS databases. The aim of this study was to investigate the association between exposure to Hg and ASD and to define the critical period of exposure. A total of 57 articles were selected for this review, with 35 articles (61.40%) identifying a positive association between ASD and Hg, while 22 articles (38.60%) did not find the same outcome. The biological samples most used to analyze Hg body burdens were hair (36.84%) and blood (36.84%). Most case-control studies found an increase in Hg levels in individuals with ASD who were exposed to a polluted environment in the post-natal period. Taken together, the studies suggest that these patients have a deficient detoxification system, and this could worsen the symptoms of the disorder. However, new studies addressing the influence of Hg on the post-natal nervous system and its relationship with ASD should be carried out.

People with Autism Spectrum Disorder Could Interact More Easily with a Robot than with a Human: Reasons and Limits.

Individuals with Autism Spectrum Disorder show deficits in communication and social interaction, as well as repetitive behaviors and restricted interests. Interacting with robots could bring benefits to this population, notably by fostering communication and social interaction. Studies even suggest that people with Autism Spectrum Disorder could interact more easily with a robot partner rather than a human partner. We will be looking at the benefits of robots and the reasons put forward to explain these results. The interest regarding robots would mainly be due to three of their characteristics: they can act as motivational tools, and they are simplified agents whose behavior is more predictable than that of a human. Nevertheless, there are still many challenges to be met in specifying the optimum conditions for using robots with individuals with Autism Spectrum Disorder.

Deep-Learning-Based Analysis Reveals a Social Behavior Deficit in Mice Exposed Prenatally to Nicotine.

Cigarette smoking during pregnancy is known to be associated with the incidence of attention-deficit/hyperactive disorder (ADHD). Recent developments in deep learning algorithms enable us to assess the behavioral phenotypes of animal models without cognitive bias during manual analysis. In this study, we established prenatal nicotine exposure (PNE) mice and evaluated their behavioral phenotypes using DeepLabCut and SimBA. We optimized the training parameters of DeepLabCut for pose estimation and succeeded in labeling a single-mouse or two-mouse model with high fidelity during free-moving behavior. We applied the trained network to analyze the behavior of the mice and found that PNE mice exhibited impulsivity and a lessened working memory, which are characteristics of ADHD. PNE mice also showed elevated anxiety and deficits in social interaction, reminiscent of autism spectrum disorder (ASD). We further examined PNE mice by evaluating adult neurogenesis in the hippocampus, which is a pathological hallmark of ASD, and demonstrated that newborn neurons were decreased, specifically in the ventral part of the hippocampus, which is reported to be related to emotional and social behaviors. These results support the hypothesis that PNE is a risk factor for comorbidity with ADHD and ASD in mice.

Sex differences in autism-like behavior and dopaminergic neurons in substantia nigra of juvenile mice prenatally exposed to valproate.

Autism spectrum disorder (ASD) is characterized by deficits in social interaction and communication and repetitive and restricted behaviors. Sex dimorphism in the brain, including midbrain dopaminergic circuits, can explain differences in social behavior impairment and stereotypic behaviors between male and female individuals with ASD. These abnormal patterns may be due to alterations in dopamine synthesis in the ventral tegmental area (VTA) and substantia nigra (SN). We used an autism-like mouse model by prenatal valproic acid (VPA) exposure. CD1 pregnant female mice were injected with 500mg/kg VPA or 0.9% NaCl as a vehicle on gestational day 12.5. In the offspring, on postnatal day 31, we examined the social and repetitive behaviors and the number of tyrosine hydroxylase (TH)-positive cells in VTA and SN by sex. Male VPA mice showed impaired social behavior and increased repetitive behaviors when compared to male vehicles. In females, we did not find statistically significant differences in social or repetitive behaviors between the groups. Male VPA mice had fewer TH+ cells in the SN than control-vehicle mice. Interestingly, no cellular changes were observed between females. This study supports the notion that sex dimorphism of certain brain regions is involved in the etiopathogenesis and clinical presentation of ASD.

Neuronal knockdown of Cullin3 as a Drosophila model of autism spectrum disorder

Mutations in Cullin-3 (Cul3), a conserved gene encoding a ubiquitin ligase, are strongly associated with autism spectrum disorder (ASD). Here, we characterize ASD-related pathologies caused by neuron-specific Cul3 knockdown in Drosophila. We confirmed that neuronal Cul3 knockdown causes short sleep, paralleling sleep disturbances in ASD. Because sleep defects and ASD are linked to metabolic dysregulation, we tested the starvation response of neuronal Cul3 knockdown flies; they starved faster and had lower triacylglyceride levels than controls, suggesting defects in metabolic homeostasis. ASD is also characterized by increased biomarkers of oxidative stress; we found that neuronal Cul3 knockdown increased sensitivity to hyperoxia, an exogenous oxidative stress. Additional hallmarks of ASD are deficits in social interactions and learning. Using a courtship suppression assay that measures social interactions and memory of prior courtship, we found that neuronal Cul3 knockdown reduced courtship and learning compared to controls. Finally, we found that neuronal Cul3 depletion alters the anatomy of the mushroom body, a brain region required for memory and sleep. Taken together, the ASD-related phenotypes of neuronal Cul3 knockdown flies establish these flies as a genetic model to study molecular and cellular mechanisms underlying ASD pathology, including metabolic and oxidative stress dysregulation and neurodevelopment.

Discrete prefrontal neuronal circuits determine repeated stress-induced behavioral phenotypes in male mice

Chronic stress is a major risk factor for psychiatric disorders, including depression. Although depression is a highly heterogeneous syndrome, it remains unclear how chronic stress drives individual differences in behavioral responses. In this study, we developed a subtyping-based approach wherein stressed male mice were divided into four subtypes based on their behavioral patterns of social interaction deficits and anhedonia, the core symptoms of psychiatric disorders. We identified three prefrontal cortical neuronal projections that regulate repeated stress-induced behavioral phenotypes. Among them, the medial prefrontal cortex (mPFC)→anterior paraventricular thalamus (aPVT) pathway determines the specific behavioral subtype that exhibits both social deficits and anhedonia. Additionally, we identified the circuit-level molecular mechanism underlying this subtype: KDM5C-mediated epigenetic repression of Shisa2 transcription in aPVT projectors in the mPFC led to social deficits and anhedonia. Thus, we provide a set of biological aspects at the cellular, molecular, and epigenetic levels that determine distinctive stress-induced behavioral phenotypes.

Differential Effects of Aripiprazole on Electroencephalography-Recorded Gamma-Band Auditory Steady-State Response, Spontaneous Gamma Oscillations and Behavior in a Schizophrenia Rat Model.

The available antipsychotics for schizophrenia (SZ) only reduce positive symptoms and do not significantly modify SZ neurobiology. This has raised the question of the robustness and translational value of methods employed during drug development. Electroencephalography (EEG)-based measures like evoked and spontaneous gamma oscillations are considered robust translational biomarkers as they can be recorded in both patients and animal models to probe a key mechanism underlying all SZ symptoms: the excitation/inhibition imbalance mediated by N-methyl-D-aspartate receptor (NMDAr) hypofunction. Understanding the effects of commercialized atypical antipsychotics on such measures could therefore contribute to developing better therapies for SZ. Yet, the effects of such drugs on these EEG readouts are unknown. Here, we studied the effect of the atypical antipsychotic aripiprazole on the gamma-band auditory steady-state response (ASSR), spontaneous gamma oscillations and behavioral features in a SZ rat model induced by the NMDAr antagonist MK-801. Interestingly, we found that aripiprazole could not normalize MK-801-induced abnormalities in ASSR, spontaneous gamma oscillations or social interaction while it still improved MK-801-induced hyperactivity. Suggesting that aripiprazole is unable to normalize electrophysiological features underlying SZ symptoms, our results might explain aripiprazole's inefficacy towards the social interaction deficit in our model but also its limited efficacy against social symptoms in patients.

Emotional Context Effects on the Rating of Ambiguous Facial Expressions in Depression and Schizophrenia Spectrum Disorders

Objective To investigate the influence of visual contextual information on emotion recognition of ambiguous facial expressions in depression and schizophrenia spectrum disorders. Method: Ambiguous facial expressions and emotional contexts representing anger, disgust, fear, joy, sadness and surprise were validated in a pre-test with healthy independent raters. Afterwards, 20 healthy participants (8 women, 12 men; mean age 24.35 ± 2.85 years), 20 participants with schizophrenia spectrum disorders (9 women, 11 men; mean age 40.25 ± 11.68 years) and 19 participants with depression (11 women, 8 men; mean age 43.74 ± 12.65 years) rated the emotional content of nine different faces in seven different emotion-suggesting contexts. The proportions of context-congruent answers and differences between emotion ratings in each context were analysed using non-parametric Kruskal-Wallis and explorative, paired Wilcoxon tests. Correlational analyses explored the influence of clinical symptoms assessed by clinician-administered scales. Results: The overall proportion of context-congruent answers did not differ between participants with depression and schizophrenia spectrum disorders compared to healthy participants. Participants with schizophrenia spectrum disorders were more susceptible to anger-suggesting contexts and participants with depression were more susceptible to fear-suggesting contexts. Differences in emotion recognition were associated with the severity of depressive, but not psychotic, symptoms. Conclusion: Despite increased susceptibility to anger-suggesting cues in schizophrenia and to fear-suggesting cues in depression, visual contextual influence remains largely consistent with healthy participants. Preserved emotional responsiveness suggests an efficacy of emotion training but emphasizes the need for additional research focusing on other factors contributing to social interaction deficits.

“When you are a parent of an autistic child, the responsibility is put on you a lot” - Learning from parents’ experiences and expectations of speech and language therapy services for autistic children in Ireland.

Autism is a neurodevelopmental disorder, characterized by deficits in social communication and interaction, restricted interests, and repetitive behaviours. Historically framed within the medical model paradigm, there are increasing calls from the autistic community to reframe autism, using the social model paradigm and embracing neurodiversity. Autistic individuals account for 1-2% of the population and access a variety of services, such as Speech & Language Therapy (SLT), which support autistic individuals' engagement in society. 
 There is a disparity of SLT services available for autistic people in Ireland and parents’ perceptions of services have not been investigated before. We aimed to investigate the parental experiences and expectations of SLT services for autistic children and make recommendations for stakeholders of autism service provision. This presentation is relevant to anyone interested in researching service users’ / parental perceptions and how they can guide the provision of care.
 This research formed a part of a Master’s degree. It was developed by a team of researchers representing SLT and social care services. The initial idea originated from clinical practice, where parents often voiced their concerns and expectations of care. 
 Interpretative Phenomenological Analysis was used as a methodological framework for this study. Participants were parents of autistic children living in the Munster province of Ireland, and they were not previously known to the research team. Individual, semi-structured interviews were carried out to identify participants’ understanding of how they made sense of their experiences. Data was analysed in depth at an individual level before group analysis took place. 
  
 Five themes emerged during group analysis: 
 1) The journey of parenting an autistic child, 
 2) The journey of experiencing services for autistic children, 
 3) The journey of navigating SLT services, 
 4) The journey of evolving therapeutic relationships and desirable clinical qualities,
 5) The journey of evolving parental expectations of changes to services for autistic children.
 Parents’ understanding of SLT services for autism was fraught with doubts about the public health system and the financial burden of accessing private services. Parents’ searches for services revealed significant wait times and barriers to access supports. Parents desired speech and language (SLTs) with clinical experience and understanding of parents’ roles in SLT. The need for reduced waiting periods for services and compassionate support for families of autistic children was also reported.
 Findings provide insight into parents’ evolving expectations and suggested changes for services for autistic children, which are important for autism service providers. Future research should focus on autistic individuals’ and SLTs experiences of SLT services for autism.

Replication of previous autism-GWAS hits suggests the association between NAA1, SORCS3, and GSDME and autism in the Han Chinese population

BackgroundAutism is a severe neurodevelopmental disorder characterized by social interaction deficits, impairments in communication, and restricted and repetitive stereotyped behavior and activities. Family and twin studies suggested an essential role of genetic factors in the etiology of autism spectrum disorder (ASD). Also, other studies found SORCS3 and GSDME (DFNA5) might be involved in brain development and susceptible to ASD. MethodsIn this study, 17 genome-wide significant SNPs reported in previous ASD genome-wide association studies (GWAS) and 7 SNPs in strong linkage disequilibrium with known ASD GWAS hits were selected to investigate the association between these SNPs and autism in the Han Chinese population. Then, 10 tagSNPs in SORCS3 and 11 tagSNPs in GSDME were selected to analyze the association between these SNPs and autism. The selected 24 SNPs and tagSNPs were genotyped using the Agena MassARRAY SNP genotyping assay in 757 Han Chinese autism trios. ResultsRs1484144 in NAA11 was significantly associated with autism; significance remained after the Bonferroni correction (P < 0.0022). Also, rs79879286, rs12154597, and rs12540919 near GSDME, as well as rs9787523 and rs3750261 in SORCS3, were nominally associated with autism. ConclusionOur study suggests that rs1484144 in NAA11 is a significant SNP for autism in the Han Chinese population, while SORCS3 and GSDME might be the susceptibility genes for autism in this population.

The Mef2c Gene Dose-Dependently Controls Hippocampal Neurogenesis and the Expression of Autism-Like Behaviors.

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disrupted Mef2c function is responsible for manifesting ASD behaviors. Overexpression of Mef2c (Mef2cOE ) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2+ in Mef2cOE DGCs. Conditional knock-out of Mef2c (Mef2ccko ) allowed neuronal commitment of Mef2ccko cells; however, Mef2ccko impaired not only dendritic arborization and spine formation but also synaptic transmission onto Mef2ccko DGCs. Moreover, the abnormal structure and function of Mef2ccko DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes.