1. Alshammery S, Patel S, Jones HF, Han VX, Gloss BS, Gold WA, Dale RC. Common targetable inflammatory pathways in brain transcriptome of autism spectrum disorders and Tourette syndrome. Frontiers in neuroscience. 2022; 16: 999346.

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR) <0.05] in the ASD dataset (n = 248) and the TS dataset (n = 156) enriched pathways involving inflammation, cytokines, signal transduction and cell signalling. Of the DEGs from the ASD and TS analyses, 23 were shared, all of which were up-regulated: interaction networks of the common protein-coding genes using STRING revealed 5 central up-regulated hub genes: CCL2, ICAM1, HMOX1, MYC, and SOCS3. Applying KEGG and Reactome analysis to the 23 common genes identified pathways involving the innate immune response such as interleukin and interferon signalling pathways. These findings bring new evidence of shared immune signalling in ASD and TS brain transcriptome, to support the overlapping symptoms that individuals with these complex disorders experience.

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2. Angell AM, Carreon ED, Akrofi JNS, Franklin MD, Taylor EE, Miller J, Crowley C, Maher SO. Challenges and Facilitators to Telehealth Occupational Therapy for Autistic Children During COVID-19. OTJR : occupation, participation and health. 2023: 15394492221142597.

Pre-pandemic, telehealth occupational therapy (OT) for autistic children appeared promising, but research was limited. The pandemic provided a unique opportunity to investigate how clinics transitioned to telehealth. The purpose of this study was to examine barriers and facilitators that influenced delivery of OT services through telehealth for autistic children during the pandemic. We conducted semi-structured qualitative interviews with 13 participants (three administrators, six OTs, and four parents of autistic children) at three Los Angeles area clinics over a 7-month period. We used narrative and thematic analysis to identify four themes. We identified (a) Challenges and (b) Facilitators to Conducting Telehealth OT, including practical strategies for successful facilitation, and (c) Negative and (d) Positive Outcomes of Conducting Telehealth OT. As telehealth will likely remain a viable means of OT service delivery in the future, our findings provide insight into ways that it can be improved and sustained.

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3. Barone R, Colombi C. Editorial: Women in psychiatry 2021: Autism. Frontiers in psychiatry. 2022; 13: 1090395.

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4. Brandi Gomes Godoy P, McWilliams L, Rodrigues da Silveira L, de Cesaro Revers Biasão M, Speggiorin Pereira Alarcão F, Seda L, Generoso Campoli R, Liang H, Divan G, Leadbitter K, Green J, Shephard E. Acceptability and feasibility of a parent-mediated social-communication therapy for young autistic children in Brazil: A qualitative implementation study of Paediatric Autism Communication Therapy. Autism : the international journal of research and practice. 2023: 13623613221144501.

Parents of autistic children and health professionals who work with autistic children in Brazil had positive views about introducing Paediatric Autism Communication Therapy as a therapy for autistic children in Brazil. The parents and clinicians also mentioned some difficulties about using Paediatric Autism Communication Therapy in Brazil. We made adaptations to Paediatric Autism Communication Therapy to address these difficulties. Paediatric Autism Communication Therapy is a therapy to support the development of social and communication skills for autistic children aged 2-10 years. The therapy is conducted with the autistic child’s parent. Paediatric Autism Communication Therapy has not been used in Brazil before. There are few therapy options available for autistic children in Brazil and we believed that Paediatric Autism Communication Therapy may be useful. We asked three groups of people in Brazil about their views of Paediatric Autism Communication Therapy, after explaining how the therapy works. Group 1 included 18 parents of autistic children aged 2-10 years. Group 2 included 20 health professionals such as psychologists who work with autistic children. Group 3 included 15 parents of autistic children aged 2-7 years who received the Paediatric Autism Communication Therapy. We learned that parents and clinicians felt that Paediatric Autism Communication Therapy would be a beneficial therapy for autistic children in Brazil. We also found out about the challenges of using Paediatric Autism Communication Therapy in Brazil. We used these findings to make small cultural adaptations to Paediatric Autism Communication Therapy to make it more suitable for Brazil.

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5. Hogendoorn E, Hartman CA, Burke SM, van Dijk MWG, Rosmalen JGM. Longitudinal relations between autistic-like features and functional somatic symptoms in adolescence. Autism : the international journal of research and practice. 2023: 13623613221143874.

Adolescents with autistic-like features frequently experience unexplained somatic symptoms too, and vice versa. We followed 2772 adolescents for 8 years, starting at 11 and ending at 19 years of age. At four different moments during this time, we asked these adolescents how often they suffered from unexplained somatic symptoms, such as stomachache and dizziness. We asked their parents to what extent the adolescents showed autistic-like features at those four moments too. Then, we assessed whether the relation between autistic-like features and unexplained somatic symptoms stayed the same between 11 and 19 years old. We also looked at whether there was a reciprocal influence. So far, most studies only looked into the relation between autistic-like features and unexplained somatic symptoms at a specific moment in time. It is important to study how this relation develops over time in adolescence, so we can improve treatment for burdening co-occurring symptoms. In our sample, adolescents who experienced many autistic symptoms also experienced many unexplained somatic symptoms. This relation stayed the same over time. There was no reciprocal influence, so higher autistic-like features did not contribute to higher unexplained somatic symptoms, or the other way around. The findings of this work tell us that in adolescents with autistic-like features it is important to be alert to the presence of unexplained somatic symptoms, and vice versa.

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6. Joseph RM, Lai ER, Bishop S, Yi J, Bauman ML, Frazier JA, Santos HP, Jr., Douglas LM, Kuban KKC, Fry RC, O’Shea TM. Comparing autism phenotypes in children born extremely preterm and born at term. Autism research : official journal of the International Society for Autism Research. 2023.

Children born preterm are at increased risk for autism spectrum disorder (ASD). There is limited knowledge about whether ASD phenotypes in children born preterm differ from children born at term. The objective of this study was to compare ASD core symptoms and associated characteristics among extremely preterm (EP) and term-born children with ASD. EP participants (n = 59) from the Extremely Low Gestational Age Newborn Study who met diagnostic criteria for ASD at approximately 10 years of age were matched with term-born participants from the Simons Simplex Collection on age, sex, spoken language level, and nonverbal IQ. Core ASD symptomatology was evaluated with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). Developmental milestones, anthropometrics, seizure disorder, and psychiatric symptoms were also investigated. The EP group had lower parent-reported symptom scores on ADI-R verbal communication, specifically stereotyped language, and restricted, repetitive behaviors. There were no between-group differences on ADI-R nonverbal communication and ADI-R reciprocal social interaction or with direct observation on the ADOS-2. The EP group was more likely to have delayed speech milestones and lower physical growth parameters. Results from female-only analyses were similar to those from whole-group analyses. In sum, behavioral presentation was similar between EP and IQ- and sex-matched term-born children assessed at age 10 years, with the exception of less severe retrospectively reported stereotyped behaviors, lower physical growth parameters, and increased delays in language milestones among EP-born children with ASD.

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7. Lee JD, Terol AK, Yoon CD, Meadan H. Parent-to-parent support among parents of children with autism: A review of the literature. Autism : the international journal of research and practice. 2023: 13623613221146444.

Parents of autistic children have long reported feelings of isolation and increased stress during and after receiving their child’s diagnosis. Increasing global prevalence of autism also calls for increased services and supports to meet the needs of these families, but most parents who live in low-resource settings still report exacerbated barriers. This may indicate the need for diversifying intervention delivery models to increase contextual fit and enhance implementation effects for different populations. For example, many parents have reported parent-to-parent (P2P) model to be a source of emotional support, advocacy, and knowledge related to their child’s diagnosis, and practical advice. However, little is known about this topic due to the lack of synthesis of relevant autism literature. To address this gap, we conducted a literature review to gain a deeper understanding of how P2P support is used. We identified 25 studies based on our inclusion and exclusion criteria, which we coded to extract variables such as demographic information of participants, types of P2P, dosage, target outcomes, and social validity. About half of studies focused on providing support groups for parents, and the other half focused on individual matching and mentoring for skill acquisition of parents. Across the included 25 studies, a total of 141 parents participated as parent mentors and 747 parents as parent mentees. We also present implications for future research.

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8. Lee T, Kim S, Kim J, Park KJ, Kim HW. Efficacy of Mobile-Based Cognitive Training Program DoBrain in Preschool Children With or Without Developmental Disabilities: A Randomized, Single-Blind, Active-Controlled Trial. Psychiatry investigation. 2022; 19(12): 1000-11.

OBJECTIVE: Mobile-based cognitive training programs can be a viable alternative to in-person interventions, but their efficacies have not been established yet. In this study, we examined the efficacy of DoBrain, a mobile-based cognitive training program designed for children with developmental disabilities (DDs), in comparison with general educational apps named Junior Naver and Kakao Kids. METHODS: Children aged 34 to 77 months were recruited and randomized at a 1:1 ratio to use DoBrain or general educational apps. Each group used the assigned app on a daily basis at home for 30 minutes for 24 weeks. Parents were instructed to help the children with the app usage. A total of 166 children completed the post-test visit (DoBrain group, n=85, 55.4±8.7 months old; general educational app group, n=81, 53.7±9.9 months old). The primary outcome was cognitive development measured by Psychoeducational Profile-Revised (PEP-R), administered at baseline and at post-test. RESULTS: DoBrain had no superior effect over general educational apps on the PEP-R Developmental Quotient. When the changes before and after app usage were compared, the DoBrain group and the general educational app group both showed declines in imitation (adjusted p=0.049 and 0.022), perception (adjusted p=0.004 and <0.001), and gross motor (adjusted p=0.003 and 0.002) domains of the PEP-R. Among the DoBrain group, children with DD showed a significantly greater gain in the eye-hand coordination domain of PEP-R compared with those without DD (adjusted p=0.047). CONCLUSION: DoBrain did not show a superior effect over general educational apps on overall cognitive development in preschool children, regardless of the presence of DD. Careful monitoring of the negative effect of mobile-based cognitive training programs is necessary.

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9. Mitchell DE, Miranda-Rottmann S, Blanchard M, Araya R. Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2023; 120(2): e2208963120.

Layer 5 (L5) pyramidal neurons receive predictive and sensory inputs in a compartmentalized manner at their apical and basal dendrites, respectively. To uncover how integration of sensory inputs is affected in autism spectrum disorders (ASD), we used two-photon glutamate uncaging to activate spines in the basal dendrites of L5 pyramidal neurons from a mouse model of Fragile X syndrome (FXS), the most common genetic cause of ASD. While subthreshold excitatory inputs integrate linearly in wild-type animals, surprisingly those with FXS summate sublinearly, contradicting what would be expected of sensory hypersensitivity classically associated with ASD. We next investigated the mechanism underlying this sublinearity by performing knockdown of the regulatory β4 subunit of BK channels, which rescued the synaptic integration, a result that was corroborated with numerical simulations. Taken together, these findings suggest that there is a differential impairment in the integration of feedforward sensory and feedback predictive inputs in L5 pyramidal neurons in FXS and potentially other forms of ASD, as a result of specifically localized subcellular channelopathies. These results challenge the traditional view that FXS and other ASD are characterized by sensory hypersensitivity, proposing instead a hyposensitivity of sensory inputs and hypersensitivity of predictive inputs onto cortical neurons.

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10. Mounzer W, Stenhoff DM, Alkhateeb JM, Al Khatib AJ. A follow-up study of early intensive behavioral intervention program for children with Autism in Syria. Scientific reports. 2023; 13(1): 70.

We examined the sustained effects of early intensive behavioral intervention (EIBI) on 66 children with autism spectrum disorder who participated in the Future Center’s EIBI program. Children were assessed using the childhood autism rating scale (CARS), autism behavior checklist (ABC), and adaptive behavior scale (ABS-Arabic) 3 years after leaving the program. Continued positive effects were observed in several areas, including adaptive behavior and autism symptoms. However, participants’ social skills might have declined on the ABS-Arabic after service withdrawal. Additionally, a significant negative association (p < .001) was found between participants' performance on the CARS and the number of weekly trials. This is encouraging, given the lack of EIBI services and regional instability. Future research should increase the sample size and use a more rigorous design.

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11. Ortner NJ. CACNA1D-Related Channelopathies: From Hypertension to Autism. Handbook of experimental pharmacology. 2023.

Tightly controlled Ca(2+) influx through voltage-gated Ca(2+) channels (Cavs) is indispensable for proper physiological function. Thus, it is not surprising that Cav loss and/or gain of function have been implicated in human pathology. Deficiency of Cav1.3 L-type Ca(2+) channels (LTCCs) causes deafness and bradycardia, whereas several genetic variants of CACNA1D, the gene encoding the pore-forming α1 subunit of Cav1.3, have been linked to various disease phenotypes, such as hypertension, congenital hypoglycemia, or autism. These variants include not only common polymorphisms associated with an increased disease risk, but also rare de novo missense variants conferring high risk. This review provides a concise summary of disease-associated CACNA1D variants, whereas the main focus lies on de novo germline variants found in individuals with a neurodevelopmental disorder of variable severity. Electrophysiological recordings revealed activity-enhancing gating changes induced by these de novo variants, and tools to predict their pathogenicity and to study the resulting pathophysiological consequences will be discussed. Despite the low number of affected patients, potential phenotype-genotype correlations and factors that could impact the severity of symptoms will be covered. Since increased channel activity is assumed as the disease-underlying mechanism, pharmacological inhibition could be a treatment option. In the absence of Cav1.3-selective blockers, dihydropyridine LTCC inhibitors clinically approved for the treatment of hypertension may be used for personalized off-label trials. Findings from in vitro studies and treatment attempts in some of the patients seem promising as outlined. Taken together, due to advances in diagnostic sequencing techniques the number of reported CACNA1D variants in human diseases is constantly rising. Evidence from in silico, in vitro, and in vivo disease models can help to predict the pathogenic potential of such variants and to guide diagnosis and treatment in the clinical practice when confronted with patients harboring CACNA1D variants.

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12. Qureshi F, Hahn J. Towards the Development of a Diagnostic Test for Autism Spectrum Disorder: Big Data Meets Metabolomics. The Canadian journal of chemical engineering. 2023; 101(1): 9-17.

Autism spectrum disorder (ASD) is defined as a neurodevelopmental disorder which results in impairments in social communications and interactions as well as repetitive behaviors. Despite current estimates showing that approximately 2.2% of children are affected in the United States, relatively little about ASD pathophysiology is known in part due to the highly heterogenous presentation of the disorder. Given the limited knowledge into the biological mechanisms governing its etiology, the diagnosis of ASD is performed exclusively based on an individual’s behavior assessed by a clinician through psychometric tools. Although there is no readily available biochemical test for ASD diagnosis, multivariate statistical methods show considerable potential for effectively leveraging multiple biochemical measurements for classification and characterization purposes. In this work, markers associated with the folate dependent one-carbon metabolism and transulfuration (FOCM/TS) pathways analyzed via both Fisher Discriminant Analysis and Support Vector Machine showed strong capability to distinguish between ASD and TD cohorts. Furthermore, using Kernel Partial Least Squares regression it was possible to assess some degree of behavioral severity from metabolomic data. While the results presented need to be replicated in independent future studies, they represent a promising avenue for uncovering clinically relevant ASD biomarkers.

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13. Ren B, Burkovetskaya M, Jung Y, Bergdolt L, Totusek S, Martinez-Cerdeno V, Stauch K, Korade Z, Dunaevsky A. Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome. Glia. 2023.

Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. While neuronal contribution to FXS has been extensively studied in both animal and human-based models of FXS, the roles of astrocytes, a type of glial cells in the brain, are largely unknown. Here, we generated a human-based FXS model via differentiation of astrocytes from human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) and characterized their development, function, and proteomic profiles. We identified shortened cell cycle, enhanced Ca(2+) signaling, impaired sterol biosynthesis, and pervasive alterations in the proteome of FXS astrocytes. Our work identified astrocytic impairments that could contribute to the pathogenesis of FXS and highlight astrocytes as a novel therapeutic target for FXS treatment.

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14. Rezayi S, Tehrani-Doost M, Shahmoradi L. Features and effects of computer-based games on cognitive impairments in children with autism spectrum disorder: an evidence-based systematic literature review. BMC psychiatry. 2023; 23(1): 2.

INTRODUCTION: Children with Autism Spectrum Disorder (ASD) have different cognitive and intelligence profiles than typical developing individuals. Some of these children need cognitive rehabilitation. This study’s main purpose is to provide a systematic review about applying computerized cognitive games for autistic children and to determine the effectiveness of such interventions. MATERIAL AND METHODS: A thorough search of the ISI Web of Science, Medline (through PubMed), Scopus, IEEE Xplore, and APA PsycInfo databases was performed for articles published from inception to May 17, 2022. RESULTS: Of 1746 papers, 28 studies were found to be eligible in this systematic review. Fifteen studies (53.57%) compared a Control Group (CG) with Experimental Groups (EGs), while 13 papers (46.42%) evaluated only the impact of the applied intervention in an experimental group. Major domains of cognitive functions are divided into five main categories: 1. Executive functions, 2. Social cognition/emotions, 3. Attention/concentration, 4. Learning and memory, and 5. Language. In 42.85% (12 studies) of the screened papers, social cognition and emotions were assessed after cognitive rehabilitation. The highest rate of effects reported by studies were related to social cognition enhancement. Of the total number of included studies, 17 studies reported a positive effect at all scales, of which nine were quasi-experimental, and seven were fully experimental. CONCLUSION: Using suitable computerized game-based solutions could enhance cognition indexes in autistic children. Hence, further investigation is needed to determine the real effectiveness of these novel technologies.

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15. Richard Williams NM, Hurt-Thaut C, Thaut MH. Novel Screening Tool and Considerations for Music Therapists Serving Autistic Individuals via Telehealth: Qualitative Results from a Survey of Clinicians’ Experiences. Journal of music therapy. 2023.

During the COVID-19 pandemic, music therapists transitioned services from in-person to telehealth due to health and safety concerns. Though online delivery of music therapy services for autistic individuals occurred prior to 2020, the number of North American music therapists using telehealth with autistic clients rose substantially during the pandemic. The current paper’s objective was to delineate music therapists’ perceptions regarding factors that helped or hindered autistic persons’ engagement in online music therapy sessions. In total, 192 participants completed the survey. Qualitative content analysis of an open-ended question identified seven overarching themes regarding the benefits and challenges of telehealth music therapy for autistic clients. Findings were used to create a screening tool to help music therapists evaluate autistic persons’ suitability for telehealth and meet the needs of those who can benefit from telehealth music therapy.

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16. Tint A, Chung H, Lai MC, Balogh R, Lin E, Durbin A, Lunsky Y. Health conditions and service use of autistic women and men: A retrospective population-based case-control study. Autism : the international journal of research and practice. 2023: 13623613221144353.

This study used administrative data from Ontario, Canada to compare the health conditions and service use of autistic women and men with adults with other developmental disabilities and with adults without developmental disabilities. Autistic women and men were more likely to have physical and mental health conditions compared to adults without developmental disabilities. Rates of health conditions were similar or lower among autistic adults compared to adults with other developmental disabilities, except more autistic adults had psychiatric conditions. Autistic women and men used higher rates of psychiatric services compared to all other groups. When comparing autistic women with same aged autistic men, sex differences were found for specific physical (Crohn’s disease/colitis, rheumatoid arthritis) and psychiatric conditions (psychotic disorders, non-psychotic disorders), as well differences in service use (emergency department visits, hospitalizations, family doctor and neurologist visits). These results further highlight the high health needs and service use of autistic women and men, as well as adults with other developmental disabilities. It is critical for future research to focus on mental health support for autistic adults and to better understand how to tailor supports to best serve autistic women.

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17. Wang N, Lv L, Huang X, Shi M, Dai Y, Wei Y, Xu B, Fu C, Huang H, Shi H, Liu Y, Hu X, Qin D. Gene editing in monogenic autism spectrum disorder: animal models and gene therapies. Frontiers in molecular neuroscience. 2022; 15: 1043018.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disease, and its diagnosis is dependent on behavioral manifestation, such as impaired reciprocal social interactions, stereotyped repetitive behaviors, as well as restricted interests. However, ASD etiology has eluded researchers to date. In the past decades, based on strong genetic evidence including mutations in a single gene, gene editing technology has become an essential tool for exploring the pathogenetic mechanisms of ASD via constructing genetically modified animal models which validates the casual relationship between genetic risk factors and the development of ASD, thus contributing to developing ideal candidates for gene therapies. The present review discusses the progress in gene editing techniques and genetic research, animal models established by gene editing, as well as gene therapies in ASD. Future research should focus on improving the validity of animal models, and reliable DNA diagnostics and accurate prediction of the functional effects of the mutation will likely be equally crucial for the safe application of gene therapies.

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18. Yaşar M, Çetin FH, Türkoğlu S, Uçar HN. The relationship between executive functions and chronotype in healthy siblings of children with autism spectrum disorder. Chronobiology international. 2023: 1-9.

The aim of this study is to examine executive functions in healthy siblings of children with autism spectrum disorder (ASD) and to evaluate the relationship between chronotype and executive functions (EF). This study included 40 healthy siblings (case group) of children with ASD and 40 healthy controls. Executive functions were evaluated by Stroop Test, Serial Digit Learning Test (SDLT) and Cancellation Test (CT). Children’s Chronotype Questionnaire (CCTQ) and Autism Spectrum Screening Questionnaire (ASSQ) were administered to parents. It was determined that the Stroop Test and CT performances of the case group were significantly worse than the control group. There was no difference in SDLT. It was determined that the total CCTQ score of the case group was significantly higher. In addition, a significant positive correlation was found between the chronotype total score and the number of false targets in the second part of CT. In the logistic regression analysis; the chronotype total score, Stroop test fifth part correction number and CT fourth part error number were determined as possible factors in the differentiation of the case and control groups. More studies are needed to evaluate the relationship between executive functions and chronotype in siblings of children with ASD.

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19. Yoon N, Huh Y, Lee H, Kim JI, Lee J, Yang CM, Jang S, Ahn YD, Oh MR, Lee DS, Kang H, Kim BN. Alterations in Social Brain Network Topology at Rest in Children With Autism Spectrum Disorder. Psychiatry investigation. 2022; 19(12): 1055-68.

OBJECTIVE: Underconnectivity in the resting brain is not consistent in autism spectrum disorder (ASD). However, it is known that the functional connectivity of the default mode network is mainly decreased in childhood ASD. This study investigated the brain network topology as the changes in the connection strength and network efficiency in childhood ASD, including the early developmental stages. METHODS: In this study, 31 ASD children aged 2-11 years were compared with 31 age and sex-matched children showing typical development. We explored the functional connectivity based on graph filtration by assessing the single linkage distance and global and nodal efficiencies using resting-state functional magnetic resonance imaging. The relationship between functional connectivity and clinical scores was also analyzed. RESULTS: Underconnectivities within the posterior default mode network subregions and between the inferior parietal lobule and inferior frontal/superior temporal regions were observed in the ASD group. These areas significantly correlated with the clinical phenotypes. The global, local, and nodal network efficiencies were lower in children with ASD than in those with typical development. In the preschool-age children (2-6 years) with ASD, the anterior-posterior connectivity of the default mode network and cerebellar connectivity were reduced. CONCLUSION: The observed topological reorganization, underconnectivity, and disrupted efficiency in the default mode network subregions and social function-related regions could be significant biomarkers of childhood ASD.

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20. Zheng Y, Prince N, van Hattem C, Garssen J, Pardo PP, Kraneveld AD. The interaction between intestinal bacterial metabolites and phosphatase and tensin homolog in autism spectrum disorder. Molecular and cellular neurosciences. 2022: 103805.

Intestinal bacteria-associated para-cresyl sulfate (pCS) and 4-ethylphenyl sulfate (4EPS) are elevated in autism spectrum disorder (ASD). Both metabolites can induce ASD-like behaviors in mice, but the molecular mechanisms are not known. Phosphatase and tensin homolog (PTEN) is a susceptibility gene for ASD. The present study investigated the relation between pCS and 4EPS and PTEN in ASD in a valproic acid (VPA)-induced murine ASD model and an in vitro LPS-activated microglial model. The VPA-induced intestinal inflammation and compromised permeability in the distal ileum was not associated with changes of PTEN expression and phosphorylation. In contrast, VPA reduced PTEN expression in the hippocampus of mice. In vitro results show that pCS and 4EPS reduced PTEN expression and derailed innate immune response of BV2 microglial cells. The PTEN inhibitor VO-OHpic did not affect innate immune response of microglial cells. In conclusion, PTEN does not play a role in intestinal inflammation and compromised permeability in VPA-induced murine model for ASD. Although pCS and 4EPS reduced PTEN expression in microglial cells, PTEN is not involved in the pCS and 4EPS-induced derailed innate immune response of microglial cells. Further studies are needed to investigate the possible involvement of reduced PTEN expression in the ASD brain regarding synapse function and neuronal connectivity.

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21. Zhou X, Wei J, Li L, Shu Z, You L, Liu Y, Zhao R, Yao J, Wang J, Luo M, Shu Y, Yuan K, Qi H. Microglial Pten safeguards postnatal integrity of the cortex and sociability. Frontiers in immunology. 2022; 13: 1059364.

Microglial abnormalities may contribute to neurodevelopmental disorders. PTEN is implicated as a susceptibility gene for autism spectrum disorders and its germline ablation in mice causes behavioral abnormalities. Here we find postnatal PTEN deletion in microglia causes deficits in sociability and novel object recognition test. Mutant mice harbor markedly more activated microglia that manifest enhanced phagocytosis. Interestingly, two-week postponement of microglia PTEN ablation leads to no social interaction defects, even though mutant microglia remain abnormal in adult animals. Disturbed neurodevelopment caused by early PTEN deletion in microglia is characterized by insufficient VGLUT1 protein in synaptosomes, likely a consequence of enhanced removal by microglia. In correlation, in vitro acute slice recordings demonstrate weakened synaptic inputs to layer 5 pyramidal neurons in the developing cortex. Therefore, microglial PTEN safeguards integrity of neural substrates underlying sociability in a developmentally determined manner.

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