Molecular Autism最新文献

{"title":"The biosocial correlates and predictors of emotion dysregulation in autistic adults compared to borderline personality disorder and nonclinical controls","authors":"Doha Bemmouna, Amine Lagzouli, Luisa Weiner","doi":"10.1186/s13229-023-00580-3","DOIUrl":"https://doi.org/10.1186/s13229-023-00580-3","url":null,"abstract":"Emotion dysregulation (ED) is a core symptom of borderline personality disorder (BPD), whose aetiology has been attributed to biosocial factors. In autism spectrum condition (ASC), although ED is prevalent and is associated with decreased well-being (e.g. self-harm, suicidality), it has been understudied, especially in adults. It is therefore crucial to further understand ED in autistic adults to improve its treatment. Our study investigates ED, its behavioural correlates (e.g. self-harm, suicidality) and biosocial predictors in autistic adults relative to BPD and nonclinical controls (NC). A total of 724 participants (ASC = 154; BPD = 111; NC = 459) completed 11 self-reported questionnaires assessing ED, ASC and BPD traits, co-occurring disorders, alexithymia, emotional vulnerability and invalidating experiences (e.g. bullying, autistic camouflaging). The occurrence of ED behavioural correlates (i.e. self-harm, history of suicide attempts, and psychiatric hospitalizations) was collected. In addition, between-groups analyses, linear regressions and machine learning (ML) models were used to identify ED predictors in each group. ED and its behavioural correlates were higher in ASC compared to NC, but milder than in BPD. While gender did not predict ED scores, autistic women had increased risk factors to ED, including sexual abuse and camouflaging. Interestingly, BPD traits, emotional vulnerability and alexithymia strongly predicted ED scores across the groups. Using ML models, sensory sensitivity and autistic camouflaging were associated with ED in ASC, and ADHD symptoms with ED in BPD. ASC and BPD diagnoses were self-reported, which did not allow us to check their accuracy. Additionally, we did not explore the transactional and the moderating/mediating relationships between the different variables. Moreover, our research is cross-sectional and cannot draw conclusions regarding the direction and causality of relationships between ED and other clinical dimensions. ED and its behavioural correlates are heightened in BPD compared to ASC and nonclinical controls. In the ASC group, there were no gender differences in ED, despite the heightened exposure of autistic women to ED risk factors. BPD traits, emotional vulnerability, and alexithymia are core to ED regardless of diagnosis. Although less central, sensory sensitivity and autistic camouflaging seem to be specific predictors of ED in autistic adults.","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"194 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138715656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is the association between mothers’ autistic traits and childhood autistic traits moderated by maternal pre-pregnancy body mass index?","authors":"Novika Purnama Sari, Alexandros Tsompanidis, Rama J. Wahab, Romy Gaillard, Ezra Aydin, Rosemary Holt, Carrie Allison, Simon Baron-Cohen, Marinus H. van IJzendoorn, Pauline W. Jansen","doi":"10.1186/s13229-023-00578-x","DOIUrl":"https://doi.org/10.1186/s13229-023-00578-x","url":null,"abstract":"Previous studies showed that there is a positive association between mothers’ and children’s autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI). The study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient, and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale in Generation R (M = 13.5 years) and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years). Higher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; βadjusted = 0.20, p < 0.01), in early childhood (Generation R; βadjusted = 0.19, p < 0.01), and in early adolescence (Generation R; βadjusted = 0.16, p < 0.01). Furthermore, a higher maternal pre-pregnancy BMI was associated with higher child autistic traits, but only in Generation R (βadjusted = 0.03, p < 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI on the association between autistic traits of mothers and children, neither in Generation R nor in CUSP. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight. We confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed.","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"184 2 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138556154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the multidimensional nature of repetitive and restricted behaviors and interests (RRBI) in autism: neuroanatomical correlates and clinical implications.","authors":"Aline Lefebvre, Nicolas Traut, Amandine Pedoux, Anna Maruani, Anita Beggiato, Monique Elmaleh, David Germanaud, Anouck Amestoy, Myriam Ly-Le Moal, Christopher Chatham, Lorraine Murtagh, Manuel Bouvard, Marianne Alisson, Marion Leboyer, Thomas Bourgeron, Roberto Toro, Guillaume Dumas, Clara Moreau, Richard Delorme","doi":"10.1186/s13229-023-00576-z","DOIUrl":"10.1186/s13229-023-00576-z","url":null,"abstract":"<p><strong>Background: </strong>Repetitive and restricted behaviors and interests (RRBI) are core symptoms of autism with a complex entity and are commonly categorized into 'motor-driven' and 'cognitively driven'. RRBI symptomatology depends on the individual's clinical environment limiting the understanding of RRBI physiology, particularly their associated neuroanatomical structures. The complex RRBI heterogeneity needs to explore the whole RRBI spectrum by integrating the clinical context [autistic individuals, their relatives and typical developing (TD) individuals]. We hypothesized that different RRBI dimensions would emerge by exploring the whole spectrum of RRBI and that these dimensions are associated with neuroanatomical signatures-involving cortical and subcortical areas.</p><p><strong>Method: </strong>A sample of 792 individuals composed of 267 autistic subjects, their 370 first-degree relatives and 155 TD individuals was enrolled in the study. We assessed the whole patterns of RRBI in each individual by using the Repetitive Behavior Scale-Revised and the Yale-Brown Obsessive Compulsive Scale. We estimated brain volumes using MRI scanner for a subsample of the subjects (n = 152, 42 ASD, 89 relatives and 13 TD). We first investigated the dimensionality of RRBI by performing a principal component analysis on all items of these scales and included all the sampling population. We then explored the relationship between RRBI-derived factors with brain volumes using linear regression models.</p><p><strong>Results: </strong>We identified 3 main factors (with 30.3% of the RRBI cumulative variance): Factor 1 (FA1, 12.7%) reflected mainly the 'motor-driven' RRBI symptoms; Factor 2 and 3 (respectively, 8.8% and 7.9%) gathered mainly Y-BOCS related items and represented the 'cognitively driven' RRBI symptoms. These three factors were significantly associated with the right/left putamen volumes but with opposite effects: FA1 was negatively associated with an increased volume of the right/left putamen conversely to FA2 and FA3 (all uncorrected p < 0.05). FA1 was negatively associated with the left amygdala (uncorrected p < 0.05), and FA2 was positively associated with the left parietal structure (uncorrected p = 0.001).</p><p><strong>Conclusion: </strong>Our results suggested 3 coherent RRBI dimensions involving the putamen commonly and other structures according to the RRBI dimension. The exploration of the putamen's integrative role in RSBI needs to be strengthened in further studies.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"45"},"PeriodicalIF":6.2,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138445402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased cerebral lactate levels in adults with autism spectrum disorders compared to non-autistic controls: a magnetic resonance spectroscopy study.","authors":"Simon Maier, Kathrin Nickel, Thomas Lange, Georg Oeltzschner, Michael Dacko, Dominique Endres, Kimon Runge, Anke Schumann, Katharina Domschke, Michalis Rousos, Ludger Tebartz van Elst","doi":"10.1186/s13229-023-00577-y","DOIUrl":"10.1186/s13229-023-00577-y","url":null,"abstract":"<p><strong>Introduction: </strong>Autism spectrum disorder (ASD) encompasses a heterogeneous group with varied phenotypes and etiologies. Identifying pathogenic subgroups could facilitate targeted treatments. One promising avenue is investigating energy metabolism, as mitochondrial dysfunction has been implicated in a subgroup of ASD. Lactate, an indicator of energy metabolic anomalies, may serve as a potential biomarker for this subgroup. This study aimed to examine cerebral lactate (Lac+) levels in high-functioning adults with ASD, hypothesizing elevated mean Lac+ concentrations in contrast to neurotypical controls (NTCs).</p><p><strong>Materials and methods: </strong>Magnetic resonance spectroscopy (MRS) was used to study cerebral Lac+ in 71 adults with ASD and NTC, focusing on the posterior cingulate cortex (PCC). After quality control, 64 ASD and 58 NTC participants remained. Lac+ levels two standard deviations above the mean of the control group were considered elevated.</p><p><strong>Results: </strong>Mean PCC Lac+ levels were significantly higher in the ASD group than in the NTC group (p = 0.028; Cohen's d = 0.404), and 9.4% of the ASD group had elevated levels as compared to 0% of the NTCs (p = 0.029). No significant correlation was found between blood serum lactate levels and MRS-derived Lac+ levels.</p><p><strong>Limitations: </strong>A cautious interpretation of our results is warranted due to a p value of 0.028. In addition, a higher than anticipated proportion of data sets had to be excluded due to poor spectral quality.</p><p><strong>Conclusion: </strong>This study confirms the presence of elevated cerebral Lac+ levels in a subgroup of adults with ASD, suggesting the potential of lactate as a biomarker for mitochondrial dysfunction in a subgroup of ASD. The lower-than-expected prevalence (20% was expected) and moderate increase require further investigation to elucidate the underlying mechanisms and relationships with mitochondrial function.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"44"},"PeriodicalIF":6.2,"publicationDate":"2023-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136398216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder.","authors":"Ana Belen Lopez-Rodriguez, Carol L Murray, John Kealy, Clodagh Towns, Andrew Roche, Arshed Nazmi, Michelle Doran, John P Lowry, Colm Cunningham","doi":"10.1186/s13229-023-00569-y","DOIUrl":"10.1186/s13229-023-00569-y","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD.</p><p><strong>Methods: </strong>We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 µg/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal-Wallis or Mann-Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p < 0.05. For correlation analyses, data were adjusted by a linear regression model.</p><p><strong>Results: </strong>Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5-48 h.</p><p><strong>Limitations: </strong>We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements.</p><p><strong>Conclusions: </strong>The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"43"},"PeriodicalIF":6.2,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10652497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134649350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau reduction attenuates autism-like features in Fmr1 knockout mice.","authors":"Shanshan Zhao, Xiangyu Jiang, Linkun Han, Yiru Jiang, Yong Wang, Jian Meng, Xiang Zhu, Xian Zhang, Hong Luo, Yun-Wu Zhang","doi":"10.1186/s13229-023-00574-1","DOIUrl":"10.1186/s13229-023-00574-1","url":null,"abstract":"<p><strong>Background: </strong>Fragile X syndrome (FXS) is a leading cause of autism spectrum disorder (ASD) and resulted from a loss of the FMR1-encoded fragile X messenger ribonucleoprotein 1 (FMRP) protein due to large CGG repeat expansions in the promoter region of the FMR1 gene. The microtubule-associated protein Tau is a promising target for Tauopathic diseases and our preliminary study found that Tau protein levels were increased in the brain of Fmr1 knockout (KO) mice, a model of FXS. However, whether Tau reduction can prevent autism-like features in Fmr1 KO mice and become a novel strategy for FXS treatment remain unknown.</p><p><strong>Methods: </strong>Tau was genetically reduced in Fmr1 KO mice through crossing Fmr1^± female mice with Mapt^± male mice. The male offspring with different genotypes were subjected to various autism-related behavioral tests, RNA sequencing, and biochemical analysis. Fmr1 KO male mice were treated with Tau-targeting antisense oligonucleotide (ASO) and then subjected to behavioral tests and biochemical analysis.</p><p><strong>Results: </strong>Tau expression was increased in the cortex of Fmr1 KO mice. Genetically reducing Tau prevented social defects, stereotyped and repetitive behavior, and spine abnormality in Fmr1 KO mice. Tau reduction also reversed increased periodic activity and partially rescued Per1 expression reduction in Fmr1 KO mice. Moreover, Tau reduction reversed compromised P38/MAPK signaling in Fmr1 KO mice. Finally, Tau-targeting ASO also effectively alleviated autism-like phenotypes and promoted P38/MAPK signaling in Fmr1 KO mice.</p><p><strong>Limitations: </strong>Our study is limited to male mice, in agreement with the higher incidence of FXS in males than females. Whether Tau reduction also exerts protection in females deserves further scrutiny. Moreover, although Tau reduction rescues impaired P38/MAPK signaling in Fmr1 KO mice, whether this is the responsible molecular mechanism requires further determination.</p><p><strong>Conclusion: </strong>Our data indicate that Tau reduction prevents autism-like phenotypes in Fmr1 KO mice. Tau may become a new target for FXS treatment.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"42"},"PeriodicalIF":6.2,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71483690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental prediction modeling based on diffusion tensor imaging uncovering age-dependent heterogeneity in early childhood autistic brain.","authors":"Xinyue Huang,&nbsp;Yating Ming,&nbsp;Weixing Zhao,&nbsp;Rui Feng,&nbsp;Yuanyue Zhou,&nbsp;Lijie Wu,&nbsp;Jia Wang,&nbsp;Jinming Xiao,&nbsp;Lei Li,&nbsp;Xiaolong Shan,&nbsp;Jing Cao,&nbsp;Xiaodong Kang,&nbsp;Huafu Chen,&nbsp;Xujun Duan","doi":"10.1186/s13229-023-00573-2","DOIUrl":"10.1186/s13229-023-00573-2","url":null,"abstract":"<p><strong>Objective: </strong>There has been increasing evidence for atypical white matter (WM) microstructure in autistic people, but findings have been divergent. The development of autistic people in early childhood is clouded by the concurrently rapid brain growth, which might lead to the inconsistent findings of atypical WM microstructure in autism. Here, we aimed to reveal the developmental nature of autistic children and delineate atypical WM microstructure throughout early childhood while taking developmental considerations into account.</p><p><strong>Method: </strong>In this study, diffusion tensor imaging was acquired from two independent cohorts, containing 91 autistic children and 100 typically developing children (TDC), aged 4-7 years. Developmental prediction modeling using support vector regression based on TDC participants was conducted to estimate the WM atypical development index of autistic children. Then, subgroups of autistic children were identified by using the k-means clustering method and were compared to each other on the basis of demographic information, WM atypical development index, and autistic trait by using two-sample t-test. Relationship of the WM atypical development index with age was estimated by using partial correlation. Furthermore, we performed threshold-free cluster enhancement-based two-sample t-test for the group comparison in WM microstructures of each subgroup of autistic children with the rematched subsets of TDC.</p><p><strong>Results: </strong>We clustered autistic children into two subgroups according to WM atypical development index. The two subgroups exhibited distinct developmental stages and age-dependent diversity. WM atypical development index was found negatively associated with age. Moreover, an inverse pattern of atypical WM microstructures and different clinical manifestations in the two stages, with subgroup 1 showing overgrowth with low level of autistic traits and subgroup 2 exhibiting delayed maturation with high level of autistic traits, were revealed.</p><p><strong>Conclusion: </strong>This study illustrated age-dependent heterogeneity in early childhood autistic children and delineated developmental stage-specific difference that ranged from an overgrowth pattern to a delayed pattern. Trial registration This study has been registered at ClinicalTrials.gov (Identifier: NCT02807766) on June 21, 2016 ( https://clinicaltrials.gov/ct2/show/NCT02807766 ).</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"41"},"PeriodicalIF":6.2,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71413090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of presentation rate on auditory processing in Rett syndrome: event-related potential study.","authors":"Daria Kostanian,&nbsp;Anna Rebreikina,&nbsp;Victoria Voinova,&nbsp;Olga Sysoeva","doi":"10.1186/s13229-023-00566-1","DOIUrl":"10.1186/s13229-023-00566-1","url":null,"abstract":"<p><strong>Background: </strong>Rett syndrome (RS) is a rare neurodevelopmental disorder characterized by mutations in the MECP2 gene. Patients with RS have severe motor abnormalities and are often unable to walk, use hands and speak. The preservation of perceptual and cognitive functions is hard to assess, while clinicians and care-givers point out that these patients need more time to process information than typically developing peers. Neurophysiological correlates of auditory processing have been also found to be distorted in RS, but sound presentation rates were relatively quick in these studies (stimulus onset asynchrony, SOA < 1000 ms). As auditory event-related potential (ERP) is typically increased with prolongation of SOA we aim to study if SOA prolongation might compensate for observed abnormalities.</p><p><strong>Methods: </strong>We presented a repetitive stimulus (1000 Hz) at three different SOAs of 900 ms, 1800 ms, and 3600 ms in children with RS (N = 24, Mean age = 9.0 ± 3.1) and their typical development (TD) peers (N = 27, Mean age = 9.7 ± 3.4) while recording 28-channels electroencephalogram, EEG. Some RS participants (n = 10) did not show clear ERP and were excluded from the analysis.</p><p><strong>Results: </strong>Major ERP components (here assessed as N1P1 and P2N1 peak-to-peak values) were smaller at SOA 900 than at longer SOAs in both groups, pointing out that the basic mechanism of adaptation in the auditory system is preserved in at least in RS patients with evident ERPs. At the same time the latencies of these components were significantly delayed in the RS than in TD. Moreover, late components (P2N1 and N2P2) were drastically reduced in Rett syndrome irrespective of the SOA, suggesting a largely affected mechanism of integration of upcoming sensory input with memory. Moreover, developmental stagnation of auditory ERP characterized patients with RS: absence of typical P2N1 enlargement and P1 and N1 shortening with age at least for shortest SOA.</p><p><strong>Limitations: </strong>We could not figure out the cause for the high percentage of no-evident ERP RS participants and our final sample of the RS group was rather small. Also, our study did not include a control clinical group.</p><p><strong>Conclusions: </strong>Thus, auditory ERPs inform us about abnormalities within auditory processing that cannot be fully overcomed by slowing presentation rate.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"40"},"PeriodicalIF":6.2,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10605980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations.","authors":"Inci S Aksoylu, Pauline Martin, Francis Robert, Krzysztof J Szkop, Nicholas E Redmond, Srirupa Bhattacharyya, Jennifer Wang, Shan Chen, Roberta L Beauchamp, Irene Nobeli, Jerry Pelletier, Ola Larsson, Vijaya Ramesh","doi":"10.1186/s13229-023-00572-3","DOIUrl":"10.1186/s13229-023-00572-3","url":null,"abstract":"<p><strong>Background: </strong>Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin.</p><p><strong>Methods: </strong>Here, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272.</p><p><strong>Results: </strong>Polysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin.</p><p><strong>Conclusions: </strong>Our work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"39"},"PeriodicalIF":6.2,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50162121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-related changes in neural responses to sensory stimulation in autism: a cross-sectional study.","authors":"Melis E Cakar, Kaitlin K Cummings, Susan Y Bookheimer, Mirella Dapretto, Shulamite A Green","doi":"10.1186/s13229-023-00571-4","DOIUrl":"10.1186/s13229-023-00571-4","url":null,"abstract":"<p><strong>Background: </strong>Sensory over-responsivity (SOR) is an impairing sensory processing challenge in autism spectrum disorder (ASD) which shows heterogenous developmental trajectories and appears to improve into adulthood in some but not all autistic individuals. However, the neural mechanisms underlying interindividual differences in these trajectories are currently unknown.</p><p><strong>Methods: </strong>Here, we used functional magnetic resonance imaging (fMRI) to investigate the association between age and neural activity linearly and nonlinearly in response to mildly aversive sensory stimulation as well as how SOR severity moderates this association. Participants included 52 ASD (14F) and 41 (13F) typically developing (TD) youth, aged 8.6-18.0 years.</p><p><strong>Results: </strong>We found that in pre-teens, ASD children showed widespread activation differences in sensorimotor, frontal and cerebellar regions compared to TD children, while there were fewer differences between ASD and TD teens. In TD youth, older age was associated with less activation in the prefrontal cortex. In contrast, in ASD youth, older age was associated with more engagement of sensory integration and emotion regulation regions. In particular, orbitofrontal and medial prefrontal cortices showed a nonlinear relationship with age in ASD, with an especially steep increase in sensory-evoked neural activity during the mid-to-late teen years. There was also an interaction between age and SOR severity in ASD youth such that these age-related trends were more apparent in youth with higher SOR.</p><p><strong>Limitations: </strong>The cross-sectional design limits causal interpretations of the data. Future longitudinal studies will be instrumental in determining how prefrontal engagement and SOR co-develop across adolescence.</p><p><strong>Conclusions: </strong>Our results suggest that enhanced recruitment of prefrontal regions may underlie age-related decreases in SOR for a subgroup of ASD youth.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"38"},"PeriodicalIF":6.2,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10566124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41205296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}