Several factors are linked to the pathophysiology of autism spectrum disorders (ASD); however, the molecular mechanisms of the condition remain unknown. As intestinal problems and gut microbiota dysbiosis are associated with ASD development and severity, recent studies have focused on elucidating the microbiota-gut-brain axis' involvement. This study aims to explore mechanisms through which gut microbiota might influence ASD. Briefly, we depleted the microbiota of conventional male BALB/cAnNCrl (Balb/c) and C57BL/6J (BL/6) mice prior to human fecal microbiota transplantation (hFMT) with samples from children with ASD or their neurotypical siblings. We found mouse strain-specific responses to ASD hFMT. Notably, Balb/c mice exhibit decreased exploratory and social behavior, and show evidence of intestinal, systemic, and central inflammation accompanied with metabolic shifts. BL/6 mice show less changes after hFMT. Our results reveal that gut microbiota alone induce changes in ASD-like behavior, and highlight the importance of mouse strain selection when investigating multifactorial conditions like ASD.

Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental condition influenced by both genetic and environmental factors, including pesticide exposure. This study aims to investigate the pathogenic mechanisms of ASD and identify potential causative pesticides by integrating bioinformatics, machine learning, network toxicology, and molecular docking approaches. A total of 156 differentially expressed genes (128 upregulated and 28 downregulated) were identified from ASD-related transcriptomic datasets. Using the LASSO algorithm, 23 key targets were initially selected. Each combination of 1-23 targets was used to construct predictive models using eight different machine learning algorithms. The Stochastic Gradient Descent (SGD) model demonstrated the best predictive performance for 20 features, which were defined as hub targets. These targets were subsequently used in a network toxicology framework to screen for associated environmental toxicants. Three pesticide candidates-epoxiconazole, flusilazole, and DEET-were identified as strongly interacting with these core targets. Molecular docking analysis further validated stable binding affinities between these pesticides and the hub targets. Functional enrichment analysis revealed significant involvement of glycosylation-related pathways, including mucin-type O-glycan biosynthesis, implicating potential mechanisms in ASD pathogenesis. Collectively, our findings highlight novel biomolecular links between pesticide exposure and ASD risk, and propose a set of candidate biomarkers and toxicants for further experimental validation and regulatory consideration.

Introduction: The effective management of irritability is a key need in young people with autism spectrum disorder (ASD). We evaluated the efficacy and safety of brexpiprazole in children and adolescents with irritability associated with ASD. Methods: This was an 8-week, phase 3, randomized, double-blind, placebo-controlled trial (NCT04174365) and 26-week, open-label extension (OLE, NCT04258839) of brexpiprazole (0.25-3 mg/day based on body weight) in children and adolescents (5-17 years) with a diagnosis of ASD, score ≥18 on the Aberrant Behavior Checklist-Irritability (ABC-I) subscale, and score ≥4 on the Clinical Global Impressions-Severity scale. Results: Of the 119 randomized participants (brexpiprazole = 60, placebo = 59), 104 completed double-blind treatment, and 95 enrolled and 70 completed the OLE. Similar reductions in mean ABC-I subscale score were seen in both groups (least-squares mean ± standard error reduction from double-blind baseline of -10.1 ± 1.3 with brexpiprazole vs -8.9 ± 1.3 with placebo). Thus, the primary endpoint did not show a significant treatment effect (LS-mean [95% confidence interval] treatment difference: -1.22 [-4.49, 2.05], p = 0.46) and the hierarchical efficacy analysis ended at this point. At the end of the OLE, participants had a mean ± SD reduction from open-label baseline of -6.1 ± 8.2 in ABC-I subscale score. During double-blind treatment, 51.7% participants treated with brexpiprazole had ≥1 treatment-emergent adverse event (TEAE) versus 35.1% with placebo; no severe or serious TEAEs were reported. The only potentially treatment-related TEAE that occurred in ≥5% of participants was somnolence (12.1% for brexpiprazole vs 5.3% for placebo). During the OLE, the most commonly reported TEAE was increased weight (n = 13, 13.7%). Conclusions: Treatment with brexpiprazole did not demonstrate significant efficacy versus placebo for the treatment of irritability associated with ASD. The safety profile was consistent with that observed in adult and adolescent patients with schizophrenia.

Integrating data science techniques, including machine learning, natural language processing, and big data analytics, has revolutionized the diagnosis and intervention landscape for Autism Spectrum Disorder (ASD). This rapid review examines these approaches' current applications, benefits, limitations, and ethical considerations while identifying key research gaps and future directions. Data-driven methodologies offer significant advantages, such as enhanced diagnostic accuracy, personalized interventions, and increased accessibility, particularly in resource-limited settings. However, challenges like data quality, algorithmic bias, and interpretability hinder widespread implementation. Additionally, ethical concerns regarding privacy, consent, and equity necessitate careful navigation. Despite these advancements, substantial research gaps remain, including the lack of diverse datasets, limited longitudinal studies, and insufficient generalizability across populations. Future studies must prioritize addressing these gaps by fostering collaboration, ensuring ethical transparency, and developing inclusive, scalable solutions to improve patient outcomes. This review underscores the transformative potential of data science in accelerating ASD care while emphasizing the need for continued innovation and responsible application.

Autism spectrum disorder (ASD) is a genetically heterogeneous syndrome characterized by repetitive, restricted, and stereotyped behaviors, along with persistent difficulties with social interaction and communication. Despite its increasing prevalence globally, the underlying pathogenic mechanisms of this complex neurodevelopmental disorder remain poorly understood. Therefore, the identification of reliable biomarkers could play a crucial role in enabling early screening and more precise classification of ASD subtypes, offering valuable insights into its physiopathology and aiding the customization of treatment or early interventions. Biogenic amines, including serotonin, histamine, dopamine, epinephrine, norepinephrine, and polyamines, are a class of organic compounds mainly produced by the decarboxylation of amino acids. A substantial portion of the genetic variation observed in ASD has been linked to genes that are either directly or indirectly involved in the metabolism of biogenic amines. Their potential involvement in ASD has become an area of growing interest due to their pleiotropic activities in the central nervous system, where they act as both neurotransmitters and neuromodulators or hormones. This review examines the role of biogenic amines in ASD, with a particular focus on genetic alterations in the enzymes responsible for their synthesis and degradation.

While the highly evolutionarily conserved hypothalamic neuropeptide, oxytocin (OT) can influence cognitive, emotional and social functions, and may have therapeutic potential in disorders with social dysfunction, it is still unclear how it acts. Here, we review the most established findings in both animal model and human studies regarding stimuli which evoke OT release, its primary functional effects and the mechanisms whereby exogenous administration influences brain and behavior. We also review progress on whether OT administration can improve social symptoms in autism spectrum disorder and schizophrenia and consider possible impediments to translational success. Importantly, we emphasize that OT acting via its extensive central or peripheral receptors primarily influences behavior indirectly through neuromodulatory interactions with classical transmitters and other peptides which themselves can independently influence behavior. We also emphasize that exogenous administration studies increasingly demonstrate peripheral effects of OT may be of greater importance than originally thought, especially involving the vagus. Overall, we propose a hierarchical model whereby OT's neuromodulatory actions influence behavior across interconnected functional domains and ultimately help to promote survival, security and sociability. Initially, OT potently facilitates attention to salient social and other important stimuli and additionally modulates cognitive, emotional and reward processing in a person- and context-dependent manner to promote interpersonal social understanding, attraction and bonds on the one hand and social group cohesion through increased conformity, altruistic punishment and moral emotions on the other. OT also increases co-operation and protection across both social domains. We hope this review and model will promote further research and help aid future translation success.

Autism spectrum disorder (ASD) is associated with various symptoms, including repetitive behaviors, restricted interests, and deficits in proper communication. Earlier studies have linked these symptoms to abnormalities in the balance between excitatory (glutamatergic signaling) and inhibitory (GABAergic signaling) neurotransmission. The present study aimed to analyze the levels of different biomarkers in children with ASD compared to neurotypical (NT) controls. The study included 80 children, of whom 40 were cases (children with ASD) and 40 were age- and sex-matched NT controls. Serum levels of GABAA, and GABAB receptors, glutamate, zinc, potassium, and calcium were measured in both groups. ASD diagnosis was verified using the Childhood Autism Rating Scale (CARS) and Autism Diagnostic Interview-Revised (ADI-R). There was a significant decrease (P < 0.001) in the median serum levels of GABAA (0.6) and GABAB receptors (2.03) in children with ASD compared to controls. Additionally, a significant increase in median serum glutamate levels was observed in ASD children (102, P < 0.001) compared to controls. Children with ASD also showed a significant reduction (P < 0.001) in median levels of all studied blood minerals compared to controls, including potassium (3.8 vs. 4.6), calcium (9.0 vs. 9.7), and zinc (57.0 vs. 92.0). The roles of GABAB and zinc as potential pathological biomarkers were investigated due to their highly significant inverse correlations with stereotypic and repetitive behaviors (ADI-R domain), with rho = -0.393 (P = 0.012) and rho = -0.488 (P = 0.001), respectively. Further analysis of pathways regulating these biomarkers may provide deeper insights into the etiology and pathophysiology of ASD, paving the way for potential therapeutic interventions.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a 1% to 2% prevalence in children. In addition to social communication deficits and restricted or repetitive behavior, ASD is often characterized by a heightened propensity for aggression. In fact, aggressive behavior is the primary reason for hospitalization in children with ASD, and current treatment options, despite some efficacy, are often associated with prominent side effects. Despite such high clinical toll, the neurobiology of aggression in ASD remains poorly understood.

The neural circuits linked to both ASD and aggression were reviewed, with the goal of identifying overlapping components to help guide future treatment development. In discussing the clinical phenotype of aggression in ASD, some of the triggers and risk factors were noted to differ from those that cause aggression in neurotypical children. Preclinical and clinical studies on the neurobiology of aggression and ASD were synthesized to combine evidence from genetics, neuroimaging, pharmacology, and circuit manipulations. Dopamine and serotonin, 2 neuromodulators that contribute to development and behavioral control, were specifically studied.

The literature indicates that the intricate interplay of the dopamine and serotonin systems has a pivotal role in shaping behavior, including the expression of aggression.

Understanding the balance between dopamine as an accelerator and serotonin as a brake may provide insights into the mechanisms of aggression in children with ASD. Although much work remains to be done, new perspectives promise to bridge the gap between human and animal studies and pinpoint the neurobiology of aggression in ASD.

One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group.

Autism spectrum disorder (ASD) is a condition that is gaining increasing interest in research and clinical fields. Due to the improvement of screening programs and diagnostic procedures, an increasing number of cases are reaching clinical attention. Despite this, the available pharmacological options for treating ASD-related symptoms are still very limited, and while a wide number of studies are focused on children or adolescents, there is a need to increase research about the treatment of ASD in adult subjects. Given this framework, this work aims to review the available literature about pharmacological treatments for ASD, from older strategies to possible new therapeutic targets for this condition, which are often poorly responsive to available resources. The literature, besides confirming the efficacy of the approved drugs for ASD, shows a lack of adequate research for several psychopharmacological treatments despite possible promising results that need to be further investigated.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with an increasing prevalence worldwide, including in Saudi Arabia. Emerging evidence suggests that biochemical markers, such as oxidative stress indicators, neurotransmitter levels, and lipid profiles, play a significant role in ASD's pathology and may also elevate cardiovascular and metabolic risks in affected individuals. This systematic review and meta-analysis synthesize current findings on these biomarkers, with a particular focus on the Saudi population, to elucidate their relationship with ASD pathology and associated health outcomes. Following the PRISMA guidelines, data from 41 studies on oxidative stress markers, neurotransmitters, lipid profiles, and immune markers were analyzed. Searches were conducted across major databases, including PubMed, Scopus, Web of Science, and Embase, and effect sizes were calculated using standardized mean differences with a 95% confidence interval. To further interpret the data, bioinformatics tools such as Reactome, Panther, and STRING were employed to analyze biomarker pathways. The results highlight a significant association between elevated oxidative stress and mitochondrial dysfunction in individuals with ASD, with profound effects on gastrointestinal and mitochondrial health. These biochemical abnormalities disrupt synaptic plasticity and drive chronic neuroinflammation, which impairs neurodevelopmental processes, contributing to the pathology of ASD. The meta-analysis reveals minimal heterogeneity (I2 = 0.02%) and limited publication bias, supporting the reliability of these associations. The findings underscore the need for a multidisciplinary approach to ASD management in Saudi Arabia, emphasizing biomarker-based diagnostics and personalized treatment strategies. Future research directions include developing individualized diagnostic and therapeutic frameworks utilizing these biomarkers to enhance ASD-related health outcomes.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation. Diagnosing ASD is complex, and the criteria for diagnosis, as well as the term ASD, have changed during the last decades. Diagnosis is made based on observation and accomplishment of specific diagnostic criteria, while a particular biomarker of ASD does not yet exist. However, studies universally report a disequilibrium in membrane lipid content, pointing to a unique neurolipid signature of ASD. This review sheds light on the possible role of cholesterol and gangliosides, complex membrane glycosphingolipids, in the development of ASD. In addition to maintaining membrane integrity, neuronal signaling, and synaptic plasticity, these lipids play a role in neurotransmitter release and calcium signaling. Evidence linking ASD to lipidome changes includes low cholesterol levels, unusual ganglioside levels, and unique metabolic profiles. ASD symptoms may be mitigated with therapeutic interventions targeting the lipid composition of membranes. However, restoring membrane equilibrium in the central nervous system remains a challenge. This review underscores the need for comprehensive research into lipid metabolism to uncover practical insights into ASD etiology and treatment as lipidomics emerges as a major area in ASD research.

The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN's mechanisms and act as a possible treatment modality. In this review we examine the VN's important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS's impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN's potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.

Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders. This study aimed to elucidate the potential ameliorating effect of postnatal administration of MSCs-derived Exo in a rat model of ASD. Male pups were divided into control (Cont), (VPA); pups of pregnant rats injected with VPA subcutaneously (S.C.) at embryonic day (ED) 13, and (VPA + Exo); pups were intravenously (I.V.) injected with MSCs-derived Exo either at postnatal day (P) 21 (adolescent VPA + Exo) or P70 (adult VPA + Exo). They were evaluated for physiological, histopathological and immunohistochemical changes of cerebellar structure, and genetic expression of PI3k and mTOR. The VPA adult group showed increased locomotor activity and impaired social activity, and anxiety. The cerebellar histological structure was disrupted in VPA groups. VPA + Exo groups showed preservation of the normal histological structure of the cerebellum. Immunohistochemical studies revealed enhanced expression of caspase-3, GFAP, Nestin, and VEGF in VPA groups beside modifying PI3K and mTOR genetic expression. MSCs-derived Exo ameliorated most of the rat cerebellar histopathological alterations and behavioral changes. Their mitigating effect could be established through their antiapoptotic, anti-inflammatory and anti-neurogenesis effect besides modifying PI3k-mTOR signaling.

The neurobiology of autism is complex, but emerging research points to potential abnormalities and alterations in neurogenesis. The aim of the present review is to describe the advances in the understanding of the role of selected neurotrophins, neuropeptides, and other compounds secreted by neuronal cells in the processes of postnatal neurogenesis in conjunction with autism. We characterize the fundamental mechanisms of neuronal cell proliferation, generation of major neuronal cell types with special emphasis on neurogenic niches - the subventricular zone and hippocampal areas. We also discuss changes in intracellular calcium levels and calcium-dependent transcription factors in the context of the regulation of neurogenesis and cell fate determination. To sum up, this review provides specific insight into the known association between alterations in the function of the entire spectrum of molecules involved in neurogenesis and the etiology of autism pathogenesis.

Many studies have demonstrated the impact of intestinal microbiota on normal brain development. Moreover, the gut microbiota (GM) is impacted by multiple endogenous and environmental factors that may promote gut dysbiosis (GD). An increasing number of studies are investigating the possible role of the GD in the development of neurological and behavioral disorders. For autism spectrum disorders (ASD), specific intestinal bacterial signatures have been identified, knowing that gastrointestinal symptoms are frequently found in ASD. In this review, the peri and post-natal factors modulating the GM are described and the specific gut bacterial signature of ASD children is detailed. Through bidirectional communication between the GM and the brain, several mechanisms are involved in the development of ASD, such as cytokine-mediated neuroinflammation and decreased production of neuroprotective factors such as short-chain fatty acids by the GM. Imbalance of certain neurotransmitters such as serotonin or gamma-aminobutyric acid could also play a role in these gut-brain interactions. Some studies show that this GD in ASD is partly reversible by treatment with pre- and probiotics, or fecal microbiota transplantation with promising results. However, certain limitations have been raised, in particular concerning the short duration of treatment, the small sample sizes and the diversity of protocols. The development of standardized therapeutics acting on GD in large cohort could rescue the gastrointestinal symptoms and behavioral impairments, as well as patient management.

Autism Spectrum Disorder (ASD) necessitates comprehensive management, addressing complex challenges in social communication, behavioral regulation, and sensory processing, for which wearable technologies offer valuable tools to monitor and support interventions. Therefore, this review explores recent advancements in wearable technology, categorizing devices based on executive function, psychomotor skills, and the behavioral/emotional/sensory domain, highlighting their potential to improve ongoing management and intervention. To ensure rigor and comprehensiveness, the review employs a PRISMA-based methodology. Specifically, literature searches were conducted across diverse databases, focusing on studies published between 2014 and 2024, to identify the most commonly used wearables in ASD research. Notably, 55.45% of the 110 devices analyzed had an undefined FDA status, 23.6% received 510(k) clearance, and only a small percentage were classified as FDA Breakthrough Devices or in the submission process. Additionally, approximately 50% of the devices utilized sensors like ECG, EEG, PPG, and EMG, highlighting their widespread use in real-time physiological monitoring. Our work comprehensively analyzes a wide array of wearable technologies, including emerging and advanced. While these technologies have the potential to transform ASD management through real-time data collection and personalized interventions, improved clinical validation and user-centered design are essential for maximizing their effectiveness and user acceptance.

Autism spectrum disorder is a complex neurodevelopmental disorder. The available medical treatment options for autism spectrum disorder are very limited. While the etiology and pathophysiology of autism spectrum disorder are still not fully understood, recent studies have suggested that wide alterations in the GABAergic, glutamatergic, cholinergic, and serotonergic systems play a key role in its development and progression. Histamine neurotransmission is known to have complex interactions with other neurotransmitters that fit perfectly into the complex etiology of this disease. Multitarget-directed compounds with an affinity for the histamine H3 receptor indicate an interesting profile of activity against autism spectrum disorder in animal models. Here, we present the results of our research on the properties of (4-piperazin-1-ylbutyl)guanidine derivatives acting on histamine H3 receptors as potential multitarget ligands. Through the virtual screening approach, we identified promising ligands among 32 non-imidazole histamine H3 receptor antagonists/inverse agonists with potential additional activity against the dopamine D2 receptor and/or cholinesterases. The virtual screening protocol integrated predictions from SwissTargetPrediction, SEA, and PPB2 tools, along with molecular docking simulations conducted using GOLD 5.3 and Glide 7.5 software. Among the selected ligands, compounds 25 and 30 blocked radioligand binding to the D2 receptor at over 50% at a screening concentration of 1 µM. Further experiments allowed us to determine the pKi value at the D2 receptor of 6.22 and 6.12 for compounds 25 and 30, respectively. Our findings suggest that some of the tested compounds could be promising multitarget-directed ligands for the further research and development of more effective treatments for autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with altered resting-state brain function. An increased excitation-inhibition (E/I) ratio is discussed as a potential pathomechanism but in-vivo evidence of disturbed neurotransmission underlying these functional alterations remains scarce. We compared rs-fMRI local activity (LCOR) between ASD (N=405, N=395) and neurotypical controls (N=473, N=474) in two independent cohorts (ABIDE1 and ABIDE2). We then tested how these LCOR alterations co-localize with specific neurotransmitter systems derived from nuclear imaging and compared them with E/I changes induced by GABAergic (midazolam) and glutamatergic medication (ketamine). Across both cohorts, ASD subjects consistently exhibited reduced LCOR, particularly in higher-order default mode network nodes, alongside increases in bilateral temporal regions, the cerebellum, and brainstem. These LCOR alterations negatively co-localized with dopaminergic (D1, D2, DAT), glutamatergic (NMDA, mGluR5), GABAergic (GABAa) and cholinergic neurotransmission (VAChT). The NMDA-antagonist ketamine, but not GABAa-potentiator midazolam, induced LCOR changes which co-localize with D1, NMDA and GABAa receptors, thereby resembling alterations observed in ASD. We find consistent local activity alterations in ASD to be spatially associated with several major neurotransmitter systems. NMDA-antagonist ketamine induced neurochemical changes similar to ASD-related alterations, supporting the notion that pharmacological modulation of the E/I balance in healthy individuals can induce ASD-like functional brain changes. These findings provide novel insights into neurophysiological mechanisms underlying ASD.

Circadian dysfunction is prevalent in neurodevelopmental disorders, particularly in autism spectrum disorder (ASD). A plethora of empirical studies demonstrate a strong correlation between ASD and circadian disruption, suggesting that modulation of circadian rhythms and the clocks could yield satisfactory advancements. Research indicates that circadian dysfunction associated with abnormal neurodevelopmental phenotypes in ASD individuals, potentially contribute to synapse plasticity disruption. Therefore, targeting circadian rhythms may emerge as a key therapeutic approach. In this study, we did a brief review of the mammalian circadian clock, and the correlation between the circadian mechanism and the pathology of ASD at multiple levels. In addition, we highlight that circadian is the target or modulator to participate in the therapeutic approaches in the management of ASD, such as phototherapy, melatonin, modulating circadian components, natural compounds, and chronotherapies. A deep understanding of the circadian clock's regulatory role in the neurodevelopmental phenotypes in ASD may inspire novel strategies for improving ASD treatment.

Autism is a complex neurodevelopmental condition characterized by repetitive behaviors, impaired social communication, and various associated conditions such as depression and anxiety. Its multifactorial etiology includes genetic, environmental, dietary, and gastrointestinal contributions. Pathologically, Autism is linked to mitochondrial dysfunction, oxidative stress, neuroinflammation, and neurotransmitter imbalances involving GABA, glutamate, dopamine, and oxytocin. Propionic acid (PRPA) is a short-chain fatty acid produced by gut bacteria, influencing central nervous system functions. Elevated PRPA levels can exacerbate Autism-related symptoms by disrupting metabolic processes and crossing the blood-brain barrier. Our research investigates the neuroprotective potential of Genistein (GNT), an isoflavone compound with known benefits in neuropsychiatric and neurodegenerative disorders, through modulation of the AC/cAMP/CREB/PKA signaling pathway and mitochondrial ETC complex (I-IV) function. In silico analyses revealed GNT's high affinity for these targets. Subsequent in vitro and in vivo experiments using a PRPA-induced rat model of autism demonstrated that GNT (40 and 80 mg/kg., orally) significantly improves locomotion, neuromuscular coordination, and cognitive functions in PRPA-treated rodents. Behavioral assessments showed reduced immobility in the forced swim test, enhanced Morris water maze performance, and restored regular locomotor activity. On a molecular level, GNT restored levels of key signaling molecules (AC, cAMP, CREB, PKA) and mitochondrial complexes (I-V), disrupted by PRPA exposure. Additionally, GNT reduced neuroinflammation and apoptosis, normalized neurotransmitter levels, and improved the complete blood count profile. Histopathological analyses confirmed that GNT ameliorated PRPA-induced brain injuries, restored normal brain morphology, reduced demyelination, and promoted neurogenesis. The study supports GNT's potential in autism treatment by modulating neural pathways, reducing inflammation, and restoring neurotransmitter balance.

Background Autism is a neurodevelopmental disorder marked by difficulties in social communication, language, restricted interests, and repetitive behaviors. Aim This study aims to identify potential risk factors for autism among children and assess their effects on early developmental skills. Methods A case-control study was conducted from September 2022 to September 2023, involving 298 children with autism (265 boys, 33 girls) aged four to 12 from the Thi-Qar Autistic Children Center and private clinics in Iraq. A control group of 300 children (150 boys, 150 girls) was also included. Data were collected through a specialized questionnaire covering demographics, neonatal history (e.g., jaundice, birth asphyxia), parental age, and developmental skills (motor milestones, speech, handwriting). Results Among the 298 children with autism enrolled, 265 (89%) were boys and 33 (11%) were girls. Children with autism had a positive family history of autism in 207 (69%) compared to 15 (5%) in the control group (p < 0.001). Paternal age over 35 years at the time of birth was noted in 159 (53%) versus 75 (25%) for the control group (p < 0.001). Maternal age over 35 showed no significant difference (p = 0.23). Hypoxia at birth was present in 153 (51%) children with autism compared to 45 (15%) in the control group (p = 0.001). Significant developmental delays were observed, including speech defects in 210 (70%) children with autism versus 15 (5%) in controls (p < 0.001). In terms of handwriting, 240 (80%) children with autism demonstrated acceptable handwriting skills, while 60 (20%) did not, compared to 264 (88%) in the control group who achieved handwriting skills, resulting in a p-value of 0.23. Conclusions The findings indicate that boys are more affected than girls, with significant risk factors including family history, paternal age, and neonatal birth asphyxia. Children with autism demonstrated marked delays in motor skills and speech defects, emphasizing the need for early detection and intervention.

There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients. Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury, but relatively less is known about the effect in pediatric populations. The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibitors as a potential adjuvant treatment for neurocognitive decline in pediatric patients with traumatic brain injury. Investigators queried PubMed to identify literature published from database inception through June 2023 describing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions. Based on preselected search criteria, 340 unique papers were selected for title and abstract screening. Thirty-two records were reviewed in full after eliminating preclinical studies and papers outside the scope of the project. In adult traumatic brain injury, we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tolerated and shows both objective and patient-reported efficacy for reducing cognitive impairment. In children, 3 papers report on 5 children recovering from traumatic brain injury, showing limited efficacy. An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group. Given its promise for efficacy in adults with traumatic brain injury and tolerability in pediatric patients, we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted.

Cultural and generational trends have increasingly favored "anti-inflammatory" action, innovating a new class of analgesic, non-steroidal anti-inflammatory drugs (NSAIDs) in the 20th century. The modern human body has been molded over evolutionary time and while acknowledging inflammation can be pathologically entwined, it also serves an important role in healthy folliculogenesis and ovulation, shaping cues that drive needed vascular change. This review argues that because of anti-inflammatory action, the cultural invention of NSAIDs represents a particular stressor on female reproductive-age bodies, interacting with natural, underlying variation and placing limits on healthy growth and development in the follicles, creating potential autism risk through hypoxia and mutagenic or epigenetic effects. Since testes are analogs to ovaries, the biological grounding extends naturally to spermatogenesis. This review suggests the introduction of over-the-counter NSAIDs in the 1980s failed to recognize the unique functioning of reproductive-age bodies, challenging the cyclical inflammation needed for healthy gamete development. NSAIDs are framed as one (notable) stressor in an anti-inflammatory era focused on taming the risks of inflammation in modern human life.

Autism spectrum disorder (ASD) is primarily characterized by core deficits in social skills, communication, and cognition and by repetitive stereotyped behaviors. These manifestations are variable between individuals, and ASD pathogenesis is complex, with over a thousand implicated genes, many epigenetic factors, and multiple environmental influences. The mesolimbic dopamine (DA) mediated brain reward system is held to play a key role, but the rapidly expanding literature reveals intricate, nuanced signaling involving a wide array of mesolimbic loci, neurotransmitters and receptor subtypes, and neuronal variants. How altered DA signaling may constitute a downstream convergence of the manifold causal origins of ASD is not well understood. A clear working framework of ASD pathogenesis may help delineate common stages and potential diagnostic and interventional opportunities. Hence, we summarize the known natural history of ASD in the context of emerging data and perspectives to update ASD reward signaling. Then, against this backdrop, we proffer a provisional framework that organizes ASD pathogenesis into successive levels, including (1) genetic and epigenetic changes, (2) disrupted mesolimbic reward signaling pathways, (3) dysregulated neurotransmitter/DA signaling, and finally, (4) altered neurocognitive and social behavior and possible antagonist/agonist based ASD interventions. This subdivision of ASD into a logical progression of potentially addressable parts may help facilitate the rational formulation of diagnostics and targeted treatments.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication, anxiety, hyperactivity, and interest restricted to specific subjects. In addition to the genetic factors, multiple environmental factors have been related to the development of ASD. Animal models can serve as crucial tools for understanding the complexity of ASD. In this study, a chemical model of ASD has been developed in zebrafish by exposing embryos to valproic acid (VPA) from 4 to 48 h post-fertilization, rearing them to the adult stage in fish water. For the first time, an integrative approach combining behavioral analysis and neurotransmitters profile has been used for determining the effects of early-life exposure to VPA both in the larval and adult stages. Larvae from VPA-treated embryos showed hyperactivity and decreased visual and vibrational escape responses, as well as an altered neurotransmitters profile, with increased glutamate and decreased acetylcholine and norepinephrine levels. Adults from VPA-treated embryos exhibited impaired social behavior characterized by larger shoal sizes and a decreased interest for their conspecifics. A neurotransmitter analysis revealed a significant decrease in dopamine and GABA levels in the brain. These results support the potential predictive validity of this model for ASD research.

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and neuro-inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that might be expected to alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction and related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, and repetitive behaviors and sensory over-responsivity in adult offspring with persistent brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-,ion channel-, and epilepsy-associated genes, in the same time frame. Our findings suggest that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction, including neuronal excitability, altered gene expression in multiple cell types, sensory functional network connectivity, and modulation of information flow. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD behaviors in adult animals without requiring long-term physical alterations to the brain. Thus, restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing both primary sensory and social behavior phenotypes, and compensatory repetitive behavior phenotypes.

The heterogeneity of autism spectrum disorder (ASD) clinically and aetiologically hinders intervention matching and prediction of outcomes. This study investigated if the behavioural, sensory, and perinatal factor profiles of autistic children could be used to identify distinct subgroups. Participants on the autism spectrum aged 2 to 17 years and their families were sourced via the Australian Autism Biobank (AAB). Latent class analysis was used to identify subgroups within this cohort, utilising twenty-six latent variables representing child's behavioural and sensory features and perinatal factors. Four distinct subgroups within the sample (n = 1168) distinguished by sensory and behavioural autism traits and exposure to perinatal determinants were identified. Class 2 and Class 4, which displayed the greatest behavioural and sensory impairment respectively, were associated with the highest perinatal factor exposure. Class 1, labelled "Most behavioural concerns and moderate sensory and behavioural skills concerns" had mixed exposure to perinatal determinants while Class 3, named "Least sensory and behavioural skills concerns" had the least perinatal determinant exposure, indicating a directly proportional correlation between severity of clinical features and perinatal factor exposure. Additionally, association between specific exposures such as maternal mental illness in Class 1 and significant behavioural concerns was recognised. Identifying distinct subgroups among autistic children can lead to development of targeted interventions and supports. Close monitoring of children exposed to specific perinatal determinants for developmental differences could assist early intervention and supports.

Autism spectrum disorder (ASD) is a developmental disorder with a rising prevalence and unknown etiology presenting with deficits in cognition and abnormal behavior. We hypothesized that the investigation of the synaptic component of prefrontal cortex may provide proteomic signatures that may identify the biological underpinnings of cognitive deficits in childhood ASD. Subcellular fractions of synaptosomes from prefrontal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of data revealed the enrichment of ASD risk genes that participate in slow maturation of the postsynaptic density (PSD) structure and function during early brain development. Proteomic analysis revealed down regulation of PSD-related proteins including AMPA and NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, and Dock9 in children with autism (FDR-adjusted P < 0.05). In contrast, PSD-related alterations were less severe or unchanged in adult individuals with ASD. Network analyses revealed glutamate receptor abnormalities. Overall, the proteomic data support the concept that idiopathic autism is a synaptopathy involving PSD-related ASD risk genes. Interruption in evolutionarily conserved slow maturation of the PSD complex in prefrontal cortex may lead to the development of ASD in a susceptible individual.

Syndromic autism spectrum conditions (ASC), such as Klinefelter syndrome, also manifest hypogonadism. Compared to the popular Extreme Male Brain theory, the Enhanced Perceptual Functioning model explains the connection between ASC, savant traits, and giftedness more seamlessly, and their co-emergence with atypical sexual differentiation. Overexcitability of primary sensory inputs generates a relative enhancement of local to global processing of stimuli, hindering the abstraction of communication signals, in contrast to the extraordinary local information processing skills in some individuals. Weaker inhibitory function through gamma-aminobutyric acid type A (GABAA) receptors and the atypicality of synapse formation lead to this difference, and the formation of unique neural circuits that process external information. Additionally, deficiency in monitoring inner sensory information leads to alexithymia (inability to distinguish one's own emotions), which can be caused by hypoactivity of estrogen and oxytocin in the interoceptive neural circuits, comprising the anterior insular and cingulate gyri. These areas are also part of the Salience Network, which switches between the Central Executive Network for external tasks and the Default Mode Network for self-referential mind wandering. Exploring the possibility that estrogen deficiency since early development interrupts GABA shift, causing sensory processing atypicality, it helps to evaluate the co-occurrence of ASC with attention deficit hyperactivity disorder, dyslexia, and schizophrenia based on phenotypic and physiological bases. It also provides clues for understanding the common underpinnings of these neurodevelopmental disorders and gifted populations.

The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.

Autism Spectrum Disorders (ASD) are principally diagnosed by three core behavioural symptoms, such as stereotyped repertoire, communication impairments and social dysfunctions. This complex pathology has been linked to abnormalities of corticostriatal and limbic circuits. Despite experimental efforts in elucidating the molecular mechanisms behind these abnormalities, a clear etiopathogenic hypothesis is still lacking. To this aim, preclinical studies can be really helpful to longitudinally study behavioural alterations resembling human symptoms and to investigate the underlying neurobiological correlates. In this regard, the BTBR T+ Itpr3tf/J (BTBR) mice are an inbred mouse strain that exhibits a pattern of behaviours well resembling human ASD-like behavioural features. In this study, the BTBR mice model was used to investigate neurochemical and biomolecular alterations, regarding Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), together with GABAergic, glutamatergic, cholinergic, dopaminergic and noradrenergic neurotransmissions and their metabolites in four different brain areas, i.e. prefrontal cortex, hippocampus, amygdala and hypothalamus. In our results, BTBR strain reported decreased noradrenaline, acetylcholine and GABA levels in prefrontal cortex, while hippocampal measurements showed reduced NGF and BDNF expression levels, together with GABA levels. Concerning hypothalamus, no differences were retrieved. As regarding amygdala, we found reduced dopamine levels, accompanied by increased dopamine metabolites in BTBR mice, together with decreased acetylcholine, NGF and GABA levels and enhanced glutamate content. Taken together, our data showed that the BTBR ASD model, beyond its face validity, is a useful tool to untangle neurotransmission alterations that could be underpinned to the heterogeneous ASD-like behaviours, highlighting the crucial role played by amygdala.

Autism spectrum disorder (ASD) is a widespread neurodevelopmental disorder with unknown etiology. Dysfunction of several brain areas including the prefrontal cortex (PFC), hippocampus, and cerebellum is involved in cognitive and behavioral deficits associated with ASD. Several studies have reported a reduction in the number of parvalbumin-immunoreactive (PV+) neurons in brain areas of ASD patients and animal models such as a shank mutant mouse model and rodents receiving fetal valproic acid (VPA) administration. Developing therapeutic interventions that restore PV interneurons can be the future therapeutic approach to ASD. The present study examined the possible effect of agmatine (AG), an endogenous NMDA antagonist, on the number of PV+ neurons in a VPA animal model of autism. The therapeutic effects of AG in ameliorating ASD-like behaviors were previously reported in VPA rats. AG was gavaged at dosages of 0.001, 0.01, and 0.1 mg/kg from gestational day (GD) 6.5 to 18.5, and the number of PV interneurons was analyzed by immunohistochemistry in the 1-month-old rats. Prenatal VPA (GD 12.5) or AG led to a decrease of PV neurons in the PFC, Cornu ammonia (CA1), and molecular layers (MLs) of the cerebellum. However, exposure to AG restored the PV population induced by VPA. AG may modify underlying neuronal mechanisms resulting in the increased survival or restoration of the PV population.

Autism spectrum disorder (ASD) is a global concern,affecting around 75 million individuals.Various factors contribute to ASD,including mercury-containing preservatives like thimerosal (Thim) found in some vaccines.This study explored whether citicoline could be a therapeutic option for Thim-induced neuronal damage in a mouse model of ASD.Additionally,the study investigated the effects of citicoline on the α7nAChRs/Akt/Nrf2/caspase-3 pathway,which may be involved in the development of ASD.

The study separated newborn mice into four groups.The control group received saline injections,while the Thim group received intramuscular injections of 3000 μg Hg/kg Thim on days 7,9,11,and 15 after birth.The two citicoline groups were administered Thim followed by intraperitoneal injections of 250 mg/kg or 500 mg/kg citicoline for three weeks.Afterward,various parameters were assessed, including growth,behavior,brain histopathology,oxidative stress,apoptotic,and inflammatory markers.

Untreated Thim-exposed mice exhibited significant brain damage,which was substantially alleviated by citicoline treatment.This beneficial effect was associated with increased expressions and concentrations of brain α7nAChRs and Akt, increased brain content of Nrf2, and the hippocampus contents of acetylcholine. Citicoline treatment decreased the brain levels of oxidative stress markers (MDA and NO),the apoptotic marker caspase-3,and pro-inflammatory markers (NF-κB,TNF-α,and IL-1β). The drug also increased the brain GPx activity.

Based on the results of this study,the α7nAChRs pathway appears to be essential for the therapeutic effectiveness of citicoline in treating Thim-induced ASD in mice.

Social communication skills, especially eye contact and joint attention, are frequently impaired in autism spectrum disorder (ASD) and predict functional outcomes. Applied behavior analysis is one of the most common evidence-based treatments for ASD, but it is not accessible to most families in low- and middle-income countries (LMICs) as it is an expensive and intensive treatment and needs to be delivered by highly specialized professionals. Parental training has emerged as an effective alternative. This is an exploratory study to assess a parental intervention group via video modeling to acquire eye contact and joint attention. Four graded measures of eye contact and joint attention (full physical prompt, partial physical prompt, gestural prompt, and independent) were assessed in 34 children with ASD and intellectual disability (ID). There was a progressive reduction in the level of prompting required over time to acquire eye contact and joint attention, as well as a positive correlation between the time of exposure to the intervention and the acquisition of abilities. This kind of parent training using video modeling to teach eye contact and joint attention skills to children with ASD and ID is a low-cost intervention that can be applied in low-resource settings.

Introduction Autism spectrum disorder (ASD) is a neurological and developmental disorder, which poses challenges to social communication and behavior, particularly affecting social functioning. Individuals with ASD face significant social challenges, including difficulty understanding social cues and body language, limited ability to engage in reciprocal social interactions, and challenges with establishing empathy. A preference for routines and repetitive behaviors limits their ability to adapt to new or unexpected social situations. These problems tend to escalate during adolescence. These often cause distress to the individual as well as the caregivers. Group-based social skills interventions (GSSIs) are a widely used and effective modality for addressing core social impairments in children with autism. This study aims to assess the impact of GSSI on the broad age group of eight to 15 years, involving parents to enhance the transferability of children's social skills. Methods This was a single-arm interventional study where 30 verbal autistic children, aged eight to 15 years, with intelligence quotient (IQ) > 70 were enrolled after utilizing the Binet Kamat Test of Intelligence (BKT) to assess IQ and the Indian Scale for Assessment of Autism (ISAA) to grade severity of autism. The children received GSSI from interdisciplinary therapists for 12 sessions, on a weekly basis, lasting 90 minutes each for a period of three months. After each therapy session, parents received summaries of each session and were delegated reinforcing homework assignments to enable generalization and maintenance of the skills taught. Outcome measures were taken at three points in time by utilizing the Social Communication Questionnaire (SCQ) and the parent-rated Social Responsiveness Scale 2 (p-SRS-2): T1: pre-therapy at the time of enrolment; T2: immediately post-therapy at the end of three months of training; and T3: long-term follow-up, three months after the end of training. Results Mean SCQ scores were as follows: T1 = 21.87, T2 = 18.57, and T3 = 18.57 (p = 0.000). This progressive decline at T1, T2, and T3 indicated a decreasing trend in the severity of difficulties in the social communication domain. Mean p-SRS-2 scores were as follows: T1 = 73.00, T2 = 64.57, and T3 = 64.30 (p < 0.0001). This declining trend at T1, T2, and T3 suggested a statistically significant decrease in the severity of difficulties faced in various social aspects tested by the p-SRS-2, i.e., social awareness, social cognition, social communication, and social motivation, along with a reduction in restricted interests and repetitive behaviors (RRBs). Very strong correlation coefficients were obtained for SCQ scores (T1-T2 = 0.921, T1-T3 = 0.921, and T2-T3 = 1.000), as well as for p-SRS-2 scores (T1-T2 = 0.743, T1-T3 = 0.746, and T2-T3 = 0.989), which reinforced the statistical significance of the data. Conclusion GSSI is an effective parent-assisted intervention for adolescents with ASD, with effects lasting up to three months post-intervention.

Autism spectrum disorder (ASD) is a multifaceted developmental condition that commonly appears during early childhood. The etiology of ASD remains multifactorial and not yet fully understood. The identification of biomarkers may provide insights into the underlying mechanisms and pathophysiology of the disorder. The present study aimed to explore the causes of ASD by investigating the key biomedical markers, trace elements, and microbiota factors between children with autism spectrum disorder (ASD) and control subjects.

Medline, PubMed, ProQuest, EMBASE, Cochrane Library, PsycINFO, Web of Science, and EMBSCO databases have been searched for publications from 2012 to 2023 with no language restrictions using the population, intervention, control, and outcome (PICO) approach. Keywords including "autism spectrum disorder," "oxytocin," "GABA," "Serotonin," "CRP," "IL-6," "Fe," "Zn," "Cu," and "gut microbiota" were used for the search. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the article quality, and a random model was used to assess the mean difference and standardized difference between ASD and the control group in all biomedical markers, trace elements, and microbiota factors.

From 76,217 records, 43 studies met the inclusion and exclusion criteria and were included in this meta-analysis. The pooled analyses showed that children with ASD had significantly lower levels of oxytocin (mean differences, MD = -45.691, 95% confidence interval, CI: -61.667, -29.717), iron (MD = -3.203, 95% CI: -4.891, -1.514), and zinc (MD = -6.707, 95% CI: -12.691, -0.722), lower relative abundance of Bifidobacterium (MD = -1.321, 95% CI: -2.403, -0.238) and Parabacteroides (MD = -0.081, 95% CI: -0.148, -0.013), higher levels of c-reactive protein, CRP (MD = 0.401, 95% CI: 0.036, 0.772), and GABA (MD = 0.115, 95% CI: 0.045, 0.186), and higher relative abundance of Bacteroides (MD = 1.386, 95% CI: 0.717, 2.055) and Clostridium (MD = 0.281, 95% CI: 0.035, 0.526) when compared with controls. The results of the overall analyses were stable after performing the sensitivity analyses. Additionally, no substantial publication bias was observed among the studies.

Children with ASD have significantly higher levels of CRP and GABA, lower levels of oxytocin, iron, and zinc, lower relative abundance of Bifidobacterium and Parabacteroides, and higher relative abundance of Faecalibacterium, Bacteroides, and Clostridium when compared with controls. These results suggest that these indicators may be a potential biomarker panel for the diagnosis or determining therapeutic targets of ASD. Furthermore, large, sample-based, and randomized controlled trials are needed to confirm these results.

Autism spectrum disorder (ASD) is a disabling psychiatric disease characterized by impairments in communication and social skills. The pathophysiology of autism is complex and not fully known. Considering the incidence of sleep disorders in individuals with ASD and the important role of orexin in sleep, it is possible to hypothesize that an alteration of the orexinergic system could be implicated in the pathogenesis of autism symptoms. The present study was conducted to investigate the effect of suvorexant [dual orexin receptor antagonists (DORAs)] on autism-like behavior in prenatally valproic acid (VPA)-exposed rats].

Wistar female rats were administered VPA [600 mg/kg, intraperitoneally (i.p.)] or normal saline (10 ml/kg, i.p.; vehicle control) on gestational day 12.5. Thirty-two male offspring were divided into four groups: Control, VPA, Suvorexant+VPA, and VPA+Risperidone. The pups were given suvorexant [20 ml/kg, by mouth/orally (p.o.)] or risperidone (1 ml/kg, p.o.) daily from postnatal day (PND) (40-54). The offspring were tested for repetitive behaviors and cognitive ability with a Y-maze task on PND 55, and social interaction was assessed by play behavior in the open field on PND 56. And anxiety with using the three-chamber social assay on PND 56.

In the Y-maze apparatus, spontaneous alteration significantly decreased in the prenatal VPA-treated rats compared to control rats showing autistic-like behavior, and 2-week suvorexant increased the alternation, indicating the beneficial effect of suvorexant. Prenatal treatment with VPA, impaired play behavior (sniffing, grooming, and darting), and increased anxiety-related behavior. Suvorexant treatment attenuated the problems in male offspring's social behavior.

Our results showed that suvorexant improved ASD-associated behaviors in the VPA-treated rats, and the orexinergic system may be associated with the pathogenesis of autism symptoms.

Oxytocin plays an important role in brain development and is associated with various neurotransmitter systems in the brain. Abnormalities in the production, secretion, and distribution of oxytocin in the brain, at least during some stages of the development, are critical for the pathogenesis of neuropsychiatric diseases, particularly in the autism spectrum disorder. The etiology of autism includes changes in local sensory and dopaminergic areas of the brain, which are also supplied by the hypothalamic sources of oxytocin. It is very important to understand their mutual relationship. In this review, the relationship of oxytocin with several components of the dopaminergic system, gamma-aminobutyric acid (GABA) inhibitory neurotransmission and their alterations in the autism spectrum disorder is discussed. Special attention has been paid to the results describing a reduced expression of inhibitory GABAergic markers in the brain in the context of dopaminergic areas in various models of autism. It is presumed that the altered GABAergic neurotransmission, due to the absence or dysfunction of oxytocin at certain developmental stages, disinhibits the dopaminergic signaling and contributes to the autism symptoms.

Gut microbiota has been linked to infant neurodevelopment. Here, an association between infant composite cognition and gut microbiota composition is established as soon as 6 months. Higher diversity and evenness characterize microbial communities of infants with composite cognition above (Inf-aboveCC) versus below (Inf-belowCC) median values. Metaproteomic and metabolomic analyses establish an association between microbial histidine ammonia lyase and infant histidine metabolome with cognition. Fecal transplantation from Inf-aboveCC versus Inf-belowCC donors into germ-free mice shows that memory, assessed by a novel object recognition test, is a transmissible trait. Furthermore, Inf-aboveCC mice are enriched in species belonging to Phocaeicola, as well as Bacteroides and Bifidobacterium, previously linked to cognition. Finally, Inf-aboveCC mice show lower fecal histidine and urocanate:histidine and urocanate:glutamate ratios in the perirhinal cortex compared to Inf-belowCC mice. Overall, these findings reveal a causative role of gut microbiota on infant cognition, pointing at the modulation of histidine metabolite levels as a potential underlying mechanism.

The mechanism underlying autism spectrum disorder (ASD) remains incompletely understood, but researchers have identified over a thousand genes involved in complex interactions within the brain, nervous, and immune systems, particularly during the mechanism of brain development. Various contributory environmental effects including circadian rhythm have also been studied in ASD. Thus, capturing the global picture of the ASD-clock network in combined form is critical.

We reconstructed the protein-protein interaction network of ASD and circadian rhythm to understand the connection between autism and the circadian clock. A graph theoretical study is undertaken to evaluate whether the network attributes are biologically realistic. The gene ontology enrichment analyses provide information about the most important biological processes.

This study takes a fresh look at metabolic mechanisms and the identification of potential key proteins/pathways (ribosome biogenesis, oxidative stress, insulin/IGF pathway, Wnt pathway, and mTOR pathway), as well as the effects of specific conditions (such as maternal stress or disruption of circadian rhythm) on the development of ASD due to environmental factors.

Understanding the relationship between circadian rhythm and ASD provides insight into the involvement of these essential pathways in the pathogenesis/etiology of ASD, as well as potential early intervention options and chronotherapeutic strategies for treating or preventing the neurodevelopmental disorder.

Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that has been diagnosed in an increasing number of children around the world. The existing data suggest that early diagnosis and intervention can improve ASD outcomes. The causes of ASD remain complex and unclear, and there are currently no clinical biomarkers for autism spectrum disorder. There is an increasing recognition that ASD might be associated with oxidative stress through several mechanisms including abnormal metabolism (lipid peroxidation) and the toxic buildup of reactive oxygen species (ROS). Glutathione acts as an antioxidant, a free radical scavenger and a detoxifying agent. This open-label pilot study investigates the tolerability and effectiveness of oral supplementation with OpitacTM gluthathione as a treatment for patients with ASD. The various aspects of glutathione OpitacTM glutathione bioavailability were examined when administered by oral routes. The absorption of glutathione from the gastrointestinal tract has been recently investigated. The results of this case series suggest that oral glutathione supplementation may improve oxidative markers, but this does not necessarily translate to the observed clinical improvement of subjects with ASD. The study reports a good safety profile of glutathione use, with stomach upset reported in four out of six subjects. This article discusses the role of the gut microbiome and redox balance in ASD and notes that a high baseline oxidative burden may make some patients poor responders to glutathione supplementation. In conclusion, an imbalance in redox reactions is only one of the many factors contributing to ASD, and further studies are necessary to investigate other factors, such as impaired neurotransmission, immune dysregulation in the brain, and mitochondrial dysfunction.