1. Chen L, Xiong XY, Yao TT, Gui LN, Luo F, Du Y, Cheng Y. Blood exosome sensing via neuronal insulin-like growth factor-1 regulates autism-related phenotypes. Pharmacological research. 2023: 106965.

The development and progression of autism spectrum disorder (ASD) is characterized by multiple complex molecular events, highlighting the importance of the prefrontal brain regions in this process. Exosomes are nanovesicles that play a critical role in intercellular communication. Peripheral systems influence brain function under both physiological and pathological conditions. We investigated whether this influence was mediated by the direct sensing of peripheral blood exosomes by brain cells. Administration of serum exosomes from rats with valproic acid-induced ASD resulted in ASD-related phenotypes in mice, whereas exosomes from normal rats did not exhibit such effects. RNA sequencing and bioinformatics analysis suggested that negative regulation of medial prefrontal cortex (mPFC) insulin-like growth factor 1 (IGF-1) by exosome-derived miR-29b-3p may contribute to these ASD-associated effects. Further evidence showed that miR-29b-3p-enriched exosomes crossed the blood-brain barrier to reach the mPFC, subsequently inducing the suppression of IGF-1 expression in neurons. Optogenetic activation of excitatory neurons in the mPFC improved behavioral abnormalities in exosome-treated mice. The addition of exogenous IGF-1 or inhibition of miR-29b-3p expression in the mPFC also rescued the ASD-related phenotypes in mice. Importantly, administration of miR-29b-3p-enriched serum exosomes from human donors with ASD into the mouse medial prefrontal cortex was sufficient to induce hallmark ASD behaviors. Together, our findings indicate that blood-brain cross-talk is crucial for ASD pathophysiology and that the brain may sense peripheral system changes through exosomes, which could serve as the basis for future neurological therapies.

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2. Hawrylycz M, Nickl-Jockschat T. Linking Neurogenetics and Functional Connectivity in Autism. Biological psychiatry. 2023; 94(10): 765-6.

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3. Huang Q, Velthuis H, Pereira AC, Ahmad J, Cooke SF, Ellis CL, Ponteduro FM, Puts NAJ, Dimitrov M, Batalle D, Wong NML, Kowalewski L, Ivin G, Daly E, Murphy DGM, McAlonan GM. Exploratory evidence for differences in GABAergic regulation of auditory processing in autism spectrum disorder. Translational psychiatry. 2023; 13(1): 320.

Altered reactivity and responses to auditory input are core to the diagnosis of autism spectrum disorder (ASD). Preclinical models implicate ϒ-aminobutyric acid (GABA) in this process. However, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. As part of a study of potential biosignatures of GABA function in ASD to inform future clinical trials, we evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD). Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABA(B)) receptor agonist. We first established that temporal mismatch negativity was comparable between participants with ASD and those with typical development (TD). Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in TD. A post hoc analysis showed that arbaclofen-elicited shift in suppression was correlated with autistic symptomatology measured using the Autism Quotient across the entire group, though not in the smaller sample of the ASD and TD group when examined separately. Thus, our results confirm: GABAergic dysfunction contributes to the neurophysiology of auditory sensory processing alterations in ASD, and can be modulated by targeting GABA(B) activity. These GABA-dependent sensory differences may be upstream of more complex autistic phenotypes.

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4. Kul M, Dağ P, Akdağ B, Kara MZ. Sociodemographic and social barriers to early detection of autism. The Turkish journal of pediatrics. 2023; 65(5): 778-88.

BACKGROUND: The increasing incidence of autism spectrum disorder (ASD) is a common finding of many studies. Early diagnosis and appropriate treatment approaches for ASD can provide favourable clinical outcomes. This study aimed to determine the factors affecting the age at diagnosis, in children with ASD. METHODS: Two hundred and two cases diagnosed with ASD were included in the study, according to the DSM-5 diagnostic criteria, at the Mersin City Training and Research Hospital Child and Adolescent Psychiatry outpatient clinics, between April 2021 and August 2022. Clinical features and sociodemographic data that may be related to early diagnosis were investigated. RESULTS: The mean age at diagnosis was 36.76 ± 15.30 months. In 71.3% of cases parents were the first to suspect that children were developmentally different. In 38.1% of the cases, at least one of the parents denied the symptoms and evaluated their child`s development as age-appropriate. It was found that 32.7% of the cases evaluated by pediatricians and 32.5% of cases evaluated by family physicians, were referred to child psychiatry examination. The present study revealed that higher educational level of the father and the middlehigh socioeconomic status, were associated with early diagnosis. There was also a positive correlation between paternal age and age at diagnosis. CONCLUSIONS: The age at diagnosis is below the target level for early diagnosis. Studies should focus on increasing awareness of health professionals and parents about ASD.

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5. Nalbant K, Erden S. Possible effects of N-acetylcysteine in autism spectrum disorders: major clinical aspects, eating behaviors, and sleeping habits. The Turkish journal of pediatrics. 2023; 65(5): 832-44.

BACKGROUND: N-acetylcysteine (NAC) is a promising agent for reducing irritability and hyperactivity and enhancing social responsiveness in children with autism spectrum disorders (ASD). This study aims to examine the effects of NAC on cardinal symptoms, eating, and sleeping habits in preschool children with autism. METHODS: The medical records of ASD patients were investigated retrospectively. 37 children with ASD who regularly received oral NAC in two divided doses per day (400-600 mg/day) for 8 weeks were included as the study group. The control group consisted of 21 children with ASD who were recommended NAC but never used it. The initial and second assessment scores after 8 weeks of regular use of the NAC group and control group on the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Children Eating Behavior Questionnaire (CEBQ), and the Sleep Habits Questionnaire (CSHQ) were compared. RESULTS: Our findings suggested that oral NAC alleviated the intensity of cardinal autistic symptoms in areas of social withdrawal, interpersonal relationships, body use, listening response, and verbal communication. Corresponding problem behaviors such as irritability, stereotypic behavior, and hyperactivity were reduced. It was determined that there was no difference between the two groups in terms of eating behaviors and sleeping habits. CONCLUSIONS: According to the results, NAC alleviated the severity of cardinal symptoms and reduced problem behaviors in autism. Additional trials with more systematic planning, controlling for confounding effects, and long-term follow-up should be provided in future studies.

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6. Narzisi A, Halladay A, Masi G, Novarino G, Lord C. Tempering expectations: considerations on the current state of stem cells therapy for autism treatment. Frontiers in psychiatry. 2023; 14: 1287879.

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7. Sartor T, Sons S, Kunina-Habenicht O, Tröster H, Kuhn JT. Demands and stress before and during the COVID-19 pandemic of parents to children with autism spectrum disorder. Frontiers in psychology. 2023; 14: 1212556.

INTRODUCTION: Parents to children with Autism Spectrum Disorder (ASD) face diverse daily demands that can lead to stress. The aim of this study was to examine to which extent stress in parents to children with ASD can be explained by daily demands before and during the COVID-19 pandemic (after lockdowns; first half of 2022), and whether there are differences between the two time periods in this regard. METHODS: Data from parents to children with ASD living in Germany from two independent questionnaire studies (before the pandemic: N = 168, during the pandemic: N = 105) were matched for comparability. Simple and multiple linear regression analyses were used to answer the research question. RESULTS: Parental stress as well as all demands examined showed higher levels during the COVID-19 pandemic than before. Significant predictors of parental stress before and during the COVID-19 pandemic were (1) the daily demands to deal with the child’s problem behavior, (2) the restriction of one’s personal way of life, and (3) the challenge to cooperate with the partner. During the COVID-19 pandemic, the child’s problem behavior was particularly relevant. It was also found that the demand to deal with stigmatizing reactions did not explain parental stress during the COVID-19 pandemic whereas before the pandemic it had been a significant predictor. DISCUSSION: Although parental stress and the demands of daily life increased during the pandemic, most of the stress can be explained by the same demands. It is suggested that the increased levels may be due to an increase in the child’s ASD symptomatology, which is why it is advisable to install therapeutic and care structures that prepare children with ASD for future crises.

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8. Schnitzler T, Fuchs T. Autism as a Disorder of Affective Empathy. Psychopathology. 2023: 1-10.

Since the first description by Leo Kanner, individuals with autism spectrum disorder (ASD) have been attributed a reduced empathy. However, it has not yet been clarified how empathy is specifically impaired in autism. Typically, scholars distinguish between the affective and the cognitive dimensions of empathy. The latter largely overlaps with the concept of the theory of mind (ToM), according to which we need internal inferences or simulations for gaining access to the hidden mental states of others. Since a deficit in ToM is a widely accepted explanation for difficulties of individuals with ASD in social interactions, limitations in cognitive empathy are accordingly assumed. Regarding affective empathy, there are contradictory results using various methods, showing an impaired affective empathy. The main aim of the paper is to present ASD primarily as a disorder of shared interpersonal and interaffective experiences and thus of affective empathy by means of a phenomenological analysis considering empirical studies. In this framework, a deficit of the ToM is accepted but criticized as a central explanatory approach for ASD since (1) it assumes a fundamental inaccessibility of other people, which does not correspond to our everyday social situations, and (2) it manifests developmentally long after the first signs of ASD, which means that its deficit cannot explain the basic autistic difficulties in social interactions.

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9. Tamada K, Takumi T. The East Asian-Specific Risk Genes in Autism Spectrum Disorder. Biological psychiatry. 2023; 94(10): 762-4.

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10. Tyagi R, Saraf TS, Canal CE. The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors. ACS pharmacology & translational science. 2023; 6(10): 1480-91.

The serotonergic psychedelic psilocybin shows efficacy in treating neuropsychiatric disorders, though the mechanism(s) underlying its therapeutic effects remain unclear. We show that a similar psychedelic tryptamine, N,N-dipropyltryptamine (DPT), completely prevents audiogenic seizures (AGS) in an Fmr1 knockout mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses (3 or 5.6 mg/kg). Despite showing in vitro that DPT is a serotonin 5-HT(2A), 5-HT(1B), and 5-HT(1A) receptor agonist (with that rank order of functional potency, determined with TRUPATH Gα/βγ biosensors), pretreatment with selective inhibitors of 5-HT(2A/2C), 5-HT(1B), or 5-HT(1A) receptors did not block DPT’s antiepileptic effects; a pan-serotonin receptor antagonist was also ineffective. Because 5-HT(1A) receptor activation blocks AGS in Fmr1 knockout mice, we performed a dose-response experiment to evaluate DPT’s engagement of 5-HT(1A) receptors in vivo. DPT elicited 5-HT(1A)-dependent effects only at doses greater than 10 mg/kg, further supporting that DPT’s antiepileptic effects were not 5-HT(1A)-mediated. We also observed that the selective sigma1 receptor antagonist, NE-100, did not impact DPT’s antiepileptic effects, suggesting DPT engagement of sigma1 receptors was not a crucial mechanism. Separately, we observed that DPT and NE-100 at high doses caused convulsions on their own that were qualitatively distinct from AGS. In conclusion, DPT dose-dependently blocked AGS in Fmr1 knockout mice, but neither serotonin nor sigma1 receptor antagonists prevented this action. Thus, DPT might have neurotherapeutic effects independent of its serotonergic psychedelic properties. However, DPT also caused seizures at high doses, showing that DPT has complex dose-dependent in vivo polypharmacology.

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11. Wang Z, Qiao D, Chen H, Zhang S, Zhang B, Zhang J, Hu X, Wang C, Cui H, Wang X, Li S. Effects of Fmr1 gene mutations on sex differences in autism-like behavior and dendritic spine development in mice and transcriptomic studies. Neuroscience. 2023.

Fragile X syndrome (FXS) is the most common single gene disorder contributing to autism spectrum disorder (ASD). Although significant sex differences are observed in FXS, few studies have focused on the phenotypic characteristics as well as the differences in brain pathological changes and gene expression in FXS by sex. Therefore, we analyzed sex differences in autism-like behavior and dendritic spine development in two-month-old male and female Fmr1 KO and C57 mice and evaluated the mechanisms at transcriptome level. Results suggest that Fmr1 KO mice display sex differences in autism-like behavior and dendritic spine density. Compared to females, male had more severe effects on anxiety, repetitive stereotype-like behaviors, and socializing, with higher dendritic spine density. Furthermore, two male-biased and five female-biased expressed genes were screened based on KEGG pathway enrichment and protein-protein interaction (PPI) analyses. In conclusion, our findings show mutations in the Fmr1 gene lead to aberrant expression of related genes and affect the sex-differentiated behavioral phenotypes of Fmr1 KO mice by affecting brain development and functional architecture, and suggest future studies should focus on including female subjects to comprehensively reflect the differentiation of FXS in both sexes and develop more precise and effective therapeutic strategies.

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