Pathophysiology Of Autism Spectrum Disorder Research Articles

Oxidative Stress in Autism Spectrum Disorder.

According to the United States Centers for Disease Control and Prevention (CDC), as of July 11, 2016, the reported average incidence of children diagnosed with an autism spectrum disorder (ASD) was 1 in 68 (1.46%) among 8-year-old children born in 2004 and living within the 11 monitoring sites' surveillance areas in the United States of America (USA) in 2012. ASD is a multifaceted neurodevelopmental disorder that is also considered a hidden disability, as, for the most part; there are no apparent morphological differences between children with ASD and typically developing children. ASD is diagnosed based upon a triad of features including impairment in socialization, impairment in language, and repetitive and stereotypic behaviors. The increasing incidence of ASD in the pediatric population and the lack of successful curative therapies make ASD one of the most challenging disorders for medicine. ASD neurobiology is thought to be associated with oxidative stress, as shown by increased levels of reactive oxygen species and increased lipid peroxidation, as well as an increase in other indicators of oxidative stress. Children with ASD diagnosis are considered more vulnerable to oxidative stress because of their imbalance in intracellular and extracellular glutathione levels and decreased glutathione reserve capacity. Several studies have suggested that the redox imbalance and oxidative stress are integral parts of ASD pathophysiology. As such, early assessment and treatment of antioxidant status may result in a better prognosis as it could decrease the oxidative stress in the brain before it can induce more irreversible brain damage. In this review, many aspects of the role of oxidative stress in ASD are discussed, taking into account that the process of oxidative stress may be a target for therapeutic interventions.

Differential Expression of Hippocampal Circular RNAs in the BTBR Mouse Model for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with unknown etiology. Recent experimental evidences suggest the contribution of non-coding RNAs (ncRNAs) in the pathophysiology of ASD. In this work, we aimed to investigate the expression profile of the ncRNA class of circular RNAs (circRNAs) in the hippocampus of the BTBR T + tf/J (BTBR) mouse model and age-matched C57BL/6J (B6) mice. Alongside, we analyzed BTBR hippocampal gene expression profile to evaluate possible correlations between the differential abundance of circular and linear gene products. From RNA sequencing data, we identified circRNAs highly modulated in BTBR mice. Thirteen circRNAs and their corresponding linear isoforms were validated by RT-qPCR analysis. The BTBR-regulated circCdh9 was better characterized in terms of molecular structure and expression, highlighting altered levels not only in the hippocampus, but also in the cerebellum, prefrontal cortex, and amygdala. Finally, gene expression analysis of the BTBR hippocampus pinpointed altered biological and molecular pathways relevant for the ASD phenotype. By comparison of circRNA and gene expression profiles, we identified 6 genes significantly regulated at either circRNA or mRNA gene products, suggesting low overall correlation between circRNA and host gene expression. In conclusion, our results indicate a consistent deregulation of circRNA expression in the hippocampus of BTBR mice. ASD-related circRNAs should be considered in functional studies to identify their contribution to the etiology of the disorder. In addition, as abundant and highly stable molecules, circRNAs represent interesting potential biomarkers for autism.

Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development

Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both disorders have strong genetic basis, and share similar social communication deficits co-occurring with impairments of reading or language. However, whether these two disorders share common genetic risks remain elusive. DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. Dock4 is important for neuronal development and social behaviors. Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties. The present study explores the molecular and cellular functions of these two DOCK4 variants on neuronal development, by comparing them with the wild-type Dock4 protein. Notably, it is revealed that both mutants of Dock4 showed decreased ability to activate not only Rac1, but also another small GTPase Rap1. Consistently, both mutants were dysfunctional for regulation of cell morphology and cytoskeleton. Using Neuro-2a cells and hippocampus neurons as models, we found that both mutants had compromised function in promoting neurite outgrowth and dendritic spine formation. Electrophysiological recordings further showed that R853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability. Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.

Gut-Amygdala Interactions in Autism Spectrum Disorders: Developmental Roles via regulating Mitochondria, Exosomes, Immunity and microRNAs.

Autism Spectrum Disorders (ASD) have long been conceived as developmental disorder. A growing body of data highlights a role for alterations in the gut in the pathoetiology and/or pathophysiology of ASD. Recent work shows alterations in the gut microbiome to have a significant impact on amygdala development in infancy, suggesting that the alterations in the gut microbiome may act to modulate not only amygdala development but how the amygdala modulates the development of the frontal cortex and other brain regions. This article reviews wide bodies of data pertaining to the developmental roles of the maternal and foetal gut and immune systems in the regulation of offspring brain development. A number of processes seem to be important in mediating how genetic, epigenetic and environmental factors interact in early development to regulate such gut-mediated changes in the amygdala, wider brain functioning and inter-area connectivity, including via regulation of microRNA (miR)-451, 14-3-3 proteins, cytochrome P450 (CYP)1B1 and the melatonergic pathways. As well as a decrease in the activity of monoamine oxidase, heightened levels of in miR-451 and CYP1B1, coupled to decreased 14-3-3 act to inhibit the synthesis of N-acetylserotonin and melatonin, contributing to the hyperserotonemia that is often evident in ASD, with consequences for mitochondria functioning and the content of released exosomes. These same factors are likely to play a role in regulating placental changes that underpin the association of ASD with preeclampsia and other perinatal risk factors, including exposure to heavy metals and air pollutants. Such alterations in placental and gut processes act to change the amygdala-driven biological underpinnings of affect-cognitive and affect-sensory interactions in the brain. Such a perspective readily incorporates previously disparate bodies of data in ASD, including the role of the mu-opioid receptor, dopamine signaling and dopamine receptors, as well as the changes occurring to oxytocin and taurine levels. This has a number of treatment implications, the most readily applicable being the utilization of sodium butyrate and melatonin.

Autism Spectrum Disorders: Role of Pre- and Post-Natal GammaDelta (γδ) T Cells and Immune Regulation.

It is widely accepted that alterations in immune functioning are an important aspect of the pathoetiology and pathophysiology of autism spectrum disorders (ASD). A relatively under-explored aspect of these alterations is the role of gammaDelta (γδ) T cells, prenatally and in the postnatal gut, which seem important hubs in driving the course of ASD. The present article describes the role of γδ T cells in ASD, including their interactions with other immune cells shown to be altered in this spectrum of conditions, including natural killer cells and mast cells. Other risk factors in ASD, such as decreased vitamins A & D, as well as toxin-associated activation of the aryl hydrocarbon receptor, may also be intimately linked to γδ T cells, and alterations in the regulation of these cells. A growing body of data has highlighted an important role for alterations in mitochondria functioning in the regulation of immune cells, including natural killer cells and mast cells. This is an area that requires investigation in γδ T cells and their putative subtypes. It is also proposed that maternal stress may act through alterations in the maternal microbiome, leading to changes in how the balance of short-chain fatty acids, such as butyrate, which may act to regulate the placenta and foetal development. Following an overview of previous research on immune, especially γδ T cells, effects in ASD, the future research implications are discussed in detail.

Targeted Biomedical Treatment for Autism Spectrum Disorders.

A diagnosis of autism spectrum disorders (ASD) represents presentations with impairment in communication and behaviour that vary considerably in their clinical manifestations and etiology as well as in their likely pathophysiology. A growing body of data indicates that the deleterious effect of oxidative stress, mitochondrial dysfunction, immune dysregulation and neuroinflammation, as well as their interconnections are important aspects of the pathophysiology of ASD. Glutathione deficiency decreases the mitochondrial protection against oxidants and tumor necrosis factor (TNF)-α; immune dysregulation and inflammation inhibit mitochondrial function through TNF-α; autoantibodies against the folate receptors underpin cerebral folate deficiency, resulting in disturbed methylation, and mitochondrial dysfunction. Such pathophysiological processes can arise from environmental and epigenetic factors as well as their combined interactions, such as environmental toxicant exposures in individuals with (epi)genetically impaired detoxification. The emerging evidence on biochemical alterations in ASD is forming the basis for treatments aimed to target its biological underpinnings, which is of some importance, given the uncertain and slow effects of the various educational interventions most commonly used. Literature-based review of the biomedical treatment options for ASD that are derived from established pathophysiological processes. Most proposed biomedical treatments show significant clinical utility only in ASD subgroups, with specified pre-treatment biomarkers that are ameliorated by the specified treatment. For example, folinic acid supplementation has positive effects in ASD patients with identified folate receptor autoantibodies, whilst the clinical utility of methylcobalamine is apparent in ASD patients with impaired methylation capacity. Mitochondrial modulating cofactors should be considered when mitochondrial dysfunction is evident, although further research is required to identify the most appropriate single or combined treatment. Multivitamins/multiminerals formulas, as well as biotin, seem appropriate following the identification of metabolic abnormalities, with doses tapered to individual requirements. A promising area, requiring further investigations, is the utilization of antipurinergic therapies, such as low dose suramin. The assessment and identification of relevant physiological alterations and targeted intervention are more likely to produce positive treatment outcomes. As such, current evidence indicates the utility of an approach based on personalized and evidence-based medicine, rather than treatment targeted to all that may not always be beneficial (primum non nocere).

Integrating Autism Spectrum Disorder Pathophysiology: Mitochondria, Vitamin A, CD38, Oxytocin, Serotonin and Melatonergic Alterations in the Placenta and Gut.

A diverse array of data has been associated with autism spectrum disorder (ASD), reflecting the complexity of its pathophysiology as well as its heterogeneity. Two important hubs have emerged, the placenta/prenatal period and the postnatal gut, with alterations in mitochondria functioning crucial in both. Factors acting to regulate mitochondria functioning in ASD across development are reviewed in this article. Decreased vitamin A, and its retinoic acid metabolites, lead to a decrease in CD38 and associated changes that underpin a wide array of data on the biological underpinnings of ASD, including decreased oxytocin, with relevance both prenatally and in the gut. Decreased sirtuins, poly-ADP ribose polymerase-driven decreases in nicotinamide adenine dinucleotide (NAD+), hyperserotonemia, decreased monoamine oxidase, alterations in 14-3-3 proteins, microRNA alterations, dysregulated aryl hydrocarbon receptor activity, suboptimal mitochondria functioning, and decreases in the melatonergic pathways are intimately linked to this. Many of the above processes may be modulating, or mediated by, alterations in mitochondria functioning. Other bodies of data associated with ASD may also be incorporated within these basic processes, including how ASD risk factors such as maternal obesity and preeclampsia, as well as more general prenatal stressors, modulate the likelihood of offspring ASD. Such a mitochondria-focussed integrated model of the pathophysiology of ASD has important preventative and treatment implications.

Prenatal Stress and Maternal Immune Dysregulation in Autism Spectrum Disorders: Potential Points for Intervention.

Genetics is a major etiological contributor to autism spectrum disorder (ASD). Environmental factors, however, also appear to contribute. ASD pathophysiology due to gene x environment is also beginning to be explored. One reason to focus on environmental factors is that they may allow opportunities for intervention or prevention. Herein, we review two such factors that have been associated with a significant proportion of ASD risk, prenatal stress exposure and maternal immune dysregulation. Maternal stress susceptibility appears to interact with prenatal stress exposure to affect offspring neurodevelopment. We also explore how maternal stress may interact with the microbiome in the neurodevelopmental setting. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. This might also be interrelated with maternal stress exposure. Animal models have been developed to explore pathophysiology targeting each of these factors. We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, and we are beginning to explore potential mitigating factors. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential targets for prevention or intervention for this subset of environmental-associated ASD cases.

Melatonin and Circadian Rhythm in Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are neurodevelopmental disorders of early childhood which are characterized by limited social-emotional reciprocity and restricted, repetitive patterns of interest and behaviors. The pathophysiology of ASD has not been fully elucidated. Dysregulation of circadian rhythm and melatonin might play a role in ASD pathogenesis. This article aims to review the relationship between melatonin, circadian rhythm and ASD in detail. Articles published in the PubMed database between 1990- 2019 were reviewed and prominent studies in the scope of the review were included. Decreased melatonin levels were detected frequently in ASD and melatonin replacement treatment for sleep disorders accompanying ASD has given satisfactory results. Similarly, circadian rhythm disorders were frequently reported in ASD, which might increase the susceptibility to ASD through their effects on synaptic plasticity in the early neurodevelopment. Mutations in the clock-controlled genes were also common in ASD. Further are required for understanding the relationship between melatonin, circadian rhythm and ASD, which will not only shed light on the role of melatonin in the etiology of ASD, but may also guide to early intervention options.

Insulin-like growth factor 1 partially rescues early developmental defects caused by SHANK2 knockdown in human neurons.

SHANK2 is a scaffold protein that serves as a protein anchor at the postsynaptic density in neurons. Genetic variants of SHANK2 are strongly associated with synaptic dysfunction and the pathophysiology of autism spectrum disorder. Recent studies indicate that early neuronal developmental defects play a role in the pathogenesis of autism spectrum disorder, and that insulin-like growth factor 1 has a positive effect on neurite development. To investigate the effects of SHANK2 knockdown on early neuronal development, we generated a sparse culture system using human induced pluripotent stem cells, which then differentiated into neural progenitor cells after 3-14 days in culture, and which were dissociated into single neurons. Neurons in the experimental group were infected with shSHANK2 lentivirus carrying a red fluorescent protein reporter (shSHANK2 group). Control neurons were infected with scrambled shControl lentivirus carrying a red fluorescent protein reporter (shControl group). Neuronal somata and neurites were reconstructed based on the lentiviral red fluorescent protein signal. Developmental dendritic and motility changes in VGLUT1+ glutamatergic neurons and TH+ dopaminergic neurons were then evaluated in both groups. Compared with shControl VGLUT1+ neurons, the dendritic length and arborizations of shSHANK2 VGLUT1+ neurons were shorter and fewer, while cell soma speed was higher. Furthermore, dendritic length and arborization were significantly increased after insulin-like growth factor 1 treatment of shSHANK2 neurons, while cell soma speed remained unaffected. These results suggest that insulin-like growth factor 1 can rescue morphological defects, but not the change in neuronal motility. Collectively, our findings demonstrate that SHANK2 deficiency perturbs early neuronal development, and that IGF1 can partially rescue the neuronal defects caused by SHANK2 knockdown. All experimental procedures and protocols were approved by the Laboratory Animal Ethics Committee of Jinan University, China (approval No. 20170228010) on February 28, 2017.

Autism Spectrum Disorder in a Child with Hunter Syndrome

Mucopolysaccharidoses (MPS) include a group of chronic and progressive lysosomal storage disorders (LSD) which are characterized by the absence or deficiency of specific lysosomal enzymes. MPS type II or Hunter Syndrome (HS) is an X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase. Although the pathophysiology of Autism Spectrum Disorders (ASDs) is unclear, multifactorial causes are thought to play an important role in their development. Here, we report a case of HS presenting with autism-related symptoms such as restricted behaviors and lack of social interaction. To our best knowledge, this is the first report of ASD in a child with HS. In our case, the most prominent symptoms such as restricted social communicative behaviors and interest, poor eye contact, unresponsiveness to his name, repetetive behaviors, and declined enjoyment in interacting with the peers emerged were considered as autism-related which are also reported in the other types of MPS, particularly in Sanfilippo disease. Taking into account that his autistic symptoms occurred developmentally up to 3 years old, we suggested that ASD, particularly in the domains of speech, language, restricted communication, and interest, poor eye contact, and repetetive behaviors may develop concurrently in children with HS. The common genetic and biological pathways, and neural links between two disorders may underlie the development of ASD in HS cases. Clinicians should consider examining for HS, when autistic-like behaviors are observed along side other physical or other developmental abnormalities.

Cell Therapy Targets for Autism Spectrum Disorders: Hopes, Challenges and Future Directions.

Autism spectrum disorders as a group of pediatric neurodevelopmental diseases is a crucial part of the worldwide disabilities which have influence in communication skills, social interactions, and ability to understand the concepts. The precise pathophysiology of autism spectrum disorders due to the abundance of involved mechanisms is unknown. Some of these involved mechanisms are related to genetic factors, chronic neuro inflammation, mitochondrial dysfunction, oxidative stress, immune dysregulation, hormonal imbalance, and environmental factors. Current main treatments for autisms are behavioral, nutritional and medical therapies, however there is not definitive treatment approach. Therein, more novel therapies are still required to improve the symptoms. Several preclinical and clinical evidence were shown that stem cell therapy is a potential treatment option for autism spectrum disorders individuals. Considering the significant factors which can affect the outcome of stem cell therapeutic effects including stem cell types, route and dosage of administration, and mechanism of activity along with selecting best animal models can be very important in performing clinical trials.

Putative shared mechanisms in autism spectrum disorders and attention deficit hyperactivity disorder, a systematic review of the role of oxidative stress

Oxidative stress is now believed to play a crucial role for neurodevelopment disorders such as autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). To review the most recent literature regarding the role of oxidative stress for the pathophysiology of ASD and ADHD, we conducted a systematic search of the relevant literature and further discuss the clinical and research implications of this knowledge. A systematic search in PubMed database retrieved 132 articles, of which 33 were included in the review. This review found relevant evidence concerning the role of oxidative status in ASD and ADHD, albeit with some contradictory findings. In order to overcome the incongruities found, more studies are needed in the study of neurodevelopmental disorders, with more thorough study designs and particular attention to the accuracy of the diagnostic tools used for the cases included.

Change in serotonergic modulation contributes to the synaptic imbalance of neuronal circuit at the prefrontal cortex in the 15q11-13 duplication mouse model of autism

The prefrontal cortex (PFC) has been extensively studied in autism spectrum disorder (ASD) in an attempt to understand the deficits in executive and other higher brain functions related to sociability and emotion. Disruption of the excitatory/inhibitory (E/I) balance of cortical circuits is thought to underlie the pathophysiology of ASD. Recently, we showed that 15q dup mice (a model for ASD with human chromosome 15q11-13 paternal duplication) exhibit disruption of the E/I balance in layer 2/3 pyramidal neurons of the somatosensory cortex due to a decrease in the number of inhibitory synapses. However, whether there is a pathological abnormality in E/I balance in the PFC of 15q dup mice remains unknown. In this study, we found that 15q dup facilitates the activity-induced LTP of glutamate synapses onto layer 5 pyramidal neurons by shifting the E/I balance to an excitatory state, which this was associated with differences in synaptic glutamatergic and GABAergic inputs onto GABAergic fast-spiking interneurons (FSINs). Furthermore, we found that FSIN excitability was well-modulated and regulated by the constitutive activation of 5-HT2 receptors in PFC microcircuits. These results provide new insights into the cellular mechanisms underlying maintenance of optimal E/I balance in the PFC.

Autism-associated mutations in the CaVβ2 calcium-channel subunit increase Ba2+-currents and lead to differential modulation by the RGK-protein Gem

Voltage-gated calcium-channels (VGCCs) are heteromers consisting of several subunits. Mutations in the genes coding for VGCC subunits have been reported to be associated with autism spectrum disorder (ASD). In a previous study, we identified electrophysiologically relevant missense mutations of CaVβ2 subunits of VGCCs. From this, we derived the hypothesis that several CaVβ2-mutations associated with ASD show common features sensitizing LTCCs and/or enhancing currents. Using a CaVβ2d backbone, we performed extensive whole-cell and single-channel patch-clamp analyses of Ba2+ currents carried by Cav1.2 pore subunits co-transfected with the previously described CaVβ2 mutations (G167S, S197F) as well as a recently identified point mutation (V2D). Furthermore, the interaction of the mutated CaVβ2d subunits with the RGK protein Gem was analyzed by co-immunoprecipitation assays and electrophysiological studies. Patch-clamp analyses revealed that all mutations increase Ba2+ currents, e.g. by decreasing inactivation or increasing fraction of active sweeps. All CaVβ2 mutations interact with Gem, but differ in the extent and characteristics of modulation by this RGK protein (e.g. decrease of fraction of active sweeps: CaVβ2d_G167S > CaVβ2d_V2D > CaVβ2d_S197F). In conclusion, patch-clamp recordings of ASD-associated CaVβ2d mutations revealed differential modulation of Ba2+ currents carried by CaV1.2 suggesting kind of an “electrophysiological fingerprint” each. The increase in current finally observed with all CaVβ2d mutations analyzed might contribute to the complex pathophysiology of ASD and by this indicate a possible underlying molecular mechanism.

Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.

The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.

Association of genes with phenotype in autism spectrum disorder.

Autism spectrum disorder (ASD) is a genetic heterogeneous neurodevelopmental disorder that is characterized by impairments in social interaction and speech development and is accompanied by stereotypical behaviors such as body rocking, hand flapping, spinning objects, sniffing and restricted behaviors. The considerable significance of the genetics associated with autism has led to the identification of many risk genes for ASD used for the probing of ASD specificity and shared cognitive features over the past few decades. Identification of ASD risk genes helps to unravel various genetic variants and signaling pathways which are involved in ASD. This review highlights the role of ASD risk genes in gene transcription and translation regulation processes, as well as neuronal activity modulation, synaptic plasticity, disrupted key biological signaling pathways, and the novel candidate genes that play a significant role in the pathophysiology of ASD. The current emphasis on autism spectrum disorders has generated new opportunities in the field of neuroscience, and further advancements in the identification of different biomarkers, risk genes, and genetic pathways can help in the early diagnosis and development of new clinical and pharmacological treatments for ASD.

Resveratrol as adjunctive therapy in treatment of irritability in children with autism: A double-blind and placebo-controlled randomized trial.

The underlying pathophysiology of autism spectrum disorder (ASD) has been linked to immune dysregulation, oxidative stress and excitation-inhibition imbalance. Among associated symptoms of ASD, management of irritability has gained considerable attention as it complicates adjustment of ASD patients and thus necessitates its pharmacological treatment. Resveratrol is a plant phytoalexin, which has been demonstrated to have neuroprotective effects through its anti-inflammatory and antioxidant properties. This double-blind, placebo-controlled randomized trial was designed to assess the potential therapeutic effects of resveratrol plus risperidone on irritability of ASD patients. Sixty-two patients were assigned randomly into two groups of resveratrol and placebo. Both groups were treated with risperidone twice daily starting at a dose of 0.5mg with a dose increase of 0.5mg per week (for the first 3weeks). Resveratrol dosage was 250mg twice per day from the beginning of the study. Using the Aberrant Behavior Checklist-Community (ABC-C), patients were assessed for ASD-related behavioural symptoms at baseline, week 5 and week 10. The frequency of adverse events was recorded using a checklist containing 25 possible side effects, including general, gastrointestinal, neurological and cardiovascular complications. Improvements in primary outcome measure (irritability) and three secondary outcome measures (lethargy/social withdrawal, stereotypic behaviour and inappropriate speech subscales) in the resveratrol group were statistically similar to those in the placebo group. The repeated measures analysis showed no time×treatment interaction on these subscale scores. In contrast, patients in the resveratrol group showed greater decline in hyperactivity/non-compliance score as a secondary outcome measure (mean difference [CI=95%]=4.51 [0.10-8.92], t=2.04; P=.04), and repeated measures analysis showed significant effect for time×treatment effect on this subscale score (F=3.81; df=1.30; P=.043). There was no significant difference in number and severity of adverse events between the two groups. This clinical trial demonstrated no significant effect for adjunctive treatment with resveratrol on irritability of patients with ASD. However, it provided preliminary evidence indicating that resveratrol could improve hyperactivity/non-compliance of ASD patients.

A perturbed gene network containing PI3K-AKT, RAS-ERK and WNT-β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity.

Hundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1–4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/β-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.

Neuropilin 2 Signaling Mediates Corticostriatal Transmission, Spine Maintenance, and Goal-Directed Learning in Mice.

The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning, and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2-/- mouse, but does not affect the intrinsic excitability of SPNs. Furthermore, conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and Semaphorin signaling.SIGNIFICANCE STATEMENT The corticostriatal pathway controls sensorimotor, learning, and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that Neuropilin 2 (Nrp2), a receptor for the axon guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs, and learning in mice. Our findings, coupled with the association of Nrp2 with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 to be a key regulator of corticostriatal development, maintenance, and function, and may lead to better understanding of neurodevelopmental disease mechanisms.