1. Allen M, Huang BS, Notaras MJ, Lodhi A, Barrio-Alonso E, Lituma PJ, Wolujewicz P, Witztum J, Longo F, Chen M, Greening DW, Klann E, Ross ME, Liston C, Colak D. Astrocytes derived from ASD individuals alter behavior and destabilize neuronal activity through aberrant Ca(2+) signaling. Molecular psychiatry. 2022.

The cellular mechanisms of autism spectrum disorder (ASD) are poorly understood. Cumulative evidence suggests that abnormal synapse function underlies many features of this disease. Astrocytes regulate several key neuronal processes, including the formation of synapses and the modulation of synaptic plasticity. Astrocyte abnormalities have also been identified in the postmortem brain tissue of ASD individuals. However, it remains unclear whether astrocyte pathology plays a mechanistic role in ASD, as opposed to a compensatory response. To address this, we combined stem cell culturing with transplantation techniques to determine disease-specific properties inherent to ASD astrocytes. We demonstrate that ASD astrocytes induce repetitive behavior as well as impair memory and long-term potentiation when transplanted into the healthy mouse brain. These in vivo phenotypes were accompanied by reduced neuronal network activity and spine density caused by ASD astrocytes in hippocampal neurons in vitro. Transplanted ASD astrocytes also exhibit exaggerated Ca(2+) fluctuations in chimeric brains. Genetic modulation of evoked Ca(2+) responses in ASD astrocytes modulates behavior and neuronal activity deficits. Thus, this study determines that astrocytes derived from ASD iPSCs are sufficient to induce repetitive behavior as well as cognitive deficit, suggesting a previously unrecognized primary role for astrocytes in ASD.

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2. Demizu Y, Matsumoto J, Yasuda Y, Ito S, Miura K, Yamamori H, Fujimoto M, Hasegawa N, Ishimaru K, Hashimoto R. Relationship between autistic traits and social functioning in healthy individuals. Neuropsychopharmacology reports. 2022.

AIM: Social functioning is influenced by various factors. Autistic traits could be one of the factors that affect social functioning. METHODS: In the present study, the relationship between autistic traits and social functioning among 755 healthy individuals was analyzed. Autistic traits were assessed with the autism-spectrum quotient. Social functioning was assessed by the social functioning scale and the social activity assessment. RESULTS: The Autism-Spectrum Quotient total score was significantly negatively correlated with the social functioning scale total and all subscales of the social functioning scale. All subscales of the Autism-Spectrum Quotient except attention to detail were significantly negatively correlated with the social functioning scale total score. However, the Autism-Spectrum Quotient was not correlated with the social activity assessment, which indicates labor functioning. CONCLUSION: Autistic traits of healthy individuals had a negative impact on situations in real life through social functioning for daily life-sustaining. The effect was not enough to affect labor functioning as indicated by working hours in healthy individuals. These findings should also be examined in individuals with autism spectrum disorder in future studies.

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3. Jiménez JA, Simon JM, Hu W, Moy SS, Harper KM, Liu CW, Lu K, Zylka MJ. Developmental pyrethroid exposure and age influence phenotypes in a Chd8 haploinsufficient autism mouse model. Scientific reports. 2022; 12(1): 5555.

Hundreds of genes have been associated with autism spectrum disorder (ASD), including loss-of-function mutations in chromodomain helicase DNA binding protein 8 (Chd8). Environmental factors also are implicated in autism risk and have the potential to exacerbate phenotypes in genetically sensitized backgrounds. Here we investigate transcriptional and behavioral phenotypes in a Chd8 haploinsufficient (Chd8(V986*/+)) mouse line exposed to the pesticide deltamethrin (DM) from conception to postnatal day 22. Vehicle-exposed Chd8(V986*/+) mice displayed ASD-associated phenotypes, including anxiety-like behavior and altered sociability, replicating a previous study with this mouse line. A core set of genes was altered in Chd8(V986*/+) mice at multiple ages, including Usp11, Wars2, Crlf2, and Eglf6, and proximity ligation data indicated direct binding of CHD8 to the 5′ region of these genes. Moreover, oligodendrocyte and neurodegenerative transcriptional phenotypes were apparent in 12 and 18 month old Chd8(V986*/+) mice. Following DM exposure, the mutant mice displayed an exacerbated phenotype in the elevated plus maze, and genes associated with vascular endothelial cells were downregulated in the cerebral cortex of older Chd8(V986*/+) animals. Our study reveals a gene x environment interaction with a Chd8 haploinsufficient mouse line and points to the importance of investigating phenotypes in ASD animal models across the lifespan.

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4. Mehinovic E, Gray T, Campbell M, Ekholm J, Wenger A, Rowell W, Grudo A, Grimwood J, Korlach J, Gurnett C, Constantino JN, Turner TN. Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy characterized by long-read sequencing. American journal of medical genetics Part A. 2022.

Currently, protein-coding de novo variants and large copy number variants have been identified as important for ~30% of individuals with autism. One approach to identify relevant variation in individuals who lack these types of events is by utilizing newer genomic technologies. In this study, highly accurate PacBio HiFi long-read sequencing was applied to a family with autism, epileptic encephalopathy, cognitive impairment, and mild dysmorphic features (two affected female siblings, unaffected parents, and one unaffected male sibling) with no known clinical variant. From our long-read sequencing data, a de novo missense variant in the KCNC2 gene (encodes Kv3.2) was identified in both affected children. This variant was phased to the paternal chromosome of origin and is likely a germline mosaic. In silico assessment revealed the variant was not in controls, highly conserved, and predicted damaging. This specific missense variant (Val473Ala) has been shown in both an ortholog and paralog of Kv3.2 to accelerate current decay, shift the voltage dependence of activation, and prevent the channel from entering a long-lasting open state. Seven additional missense variants have been identified in other individuals with neurodevelopmental disorders (p = 1.03 × 10(-5) ). KCNC2 is most highly expressed in the brain; in particular, in the thalamus and is enriched in GABAergic neurons. Long-read sequencing was useful in discovering the relevant variant in this family with autism that had remained a mystery for several years and will potentially have great benefits in the clinic once it is widely available.

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5. Parker KJ. Leveraging a translational research approach to drive diagnostic and treatment advances for autism. Molecular psychiatry. 2022.

Autism spectrum disorder (ASD) is a prevalent and poorly understood neurodevelopmental disorder. There are currently no laboratory-based diagnostic tests to detect ASD, nor are there any disease-modifying medications that effectively treat ASD’s core behavioral symptoms. Scientific progress has been impeded, in part, by overreliance on model organisms that fundamentally lack the sophisticated social and cognitive abilities essential for modeling ASD. We therefore saw significant value in studying naturally low-social rhesus monkeys to model human social impairment, taking advantage of a large outdoor-housed colony for behavioral screening and biomarker identification. Careful development and validation of our animal model, combined with a strong commitment to evaluating the translational utility of our preclinical findings directly in patients with ASD, yielded a robust neurochemical marker (cerebrospinal fluid vasopressin concentration) of trans-primate social impairment and a first-in-class medication (intranasal vasopressin) shown in a small phase 2a pilot trial to improve social abilities in children with ASD. This translational research approach stands to advance our understanding of ASD in a manner not readily achievable with existing animal models, and can be adapted to investigate a variety of other human brain disorders which currently lack valid preclinical options, thereby streamlining translation and amplifying clinical impact more broadly.

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6. Stromberg MH, Rubtsova A, Sales J, McGee R. Impact of Developmental Disability on Frequent School Absenteeism in US Children Aged 6 to 17 Years: National Survey of Children’s Health, 2016 to 2017. The Journal of school health. 2022.

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7. Volkmar FR, Koegel LK. Editorial 2021: A Year in Review. Journal of autism and developmental disorders. 2022; 52(5): 1903-7.

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