Molecular Autism最新文献

{"title":"A systematic review of statistical learning in autism spectrum disorder.","authors":"Rebecca R Bell, Hannah R Thomas, Jenny R Saffran, Inge-Marie Eigsti","doi":"10.1186/s13229-025-00697-7","DOIUrl":"10.1186/s13229-025-00697-7","url":null,"abstract":"<p><p>Statistical learning, the ability to detect and extract statistical regularities from the environment, has been proposed as a key mechanism underlying language, social, and cognitive development. Numerous studies have examined statistical learning abilities in autistic individuals to test the hypothesis that differences contribute to the behavioral presentation of autism spectrum disorder (ASD). Findings have been inconsistent, with variations in methodology, sensory modality, and participant characteristics complicating the interpretation of results. The current study presents a systematic review of statistical, implicit, and procedural learning studies in autism, considering how statistical learning abilities vary across (a) modality (e.g., auditory versus visual), (b) methodology (e.g., behavioral versus neuroimaging), and (c) task design, and considering the influence of language and cognitive abilities. Results across 37 studies in visual and auditory modalities indicate few behavioral differences in statistical learning abilities (with the exception of slowed reaction times in autism), and that learning may benefit from extended exposure and explicit cues. In contrast, neuroimaging findings reveal substantial variability in the neural mechanisms implicated in these tasks, with evidence suggesting compensatory cognitive processing in some autistic samples. Individual differences in language, cognitive abilities, and autism-related traits strongly influence statistical learning outcomes. Significant gaps remain, particularly in the inclusion of minimally verbal individuals and those with intellectual disabilities. Methodological heterogeneity, skewed gender and sociodemographic sample characteristics, and inconsistent neural findings highlight the need for more standardized approaches in future research. Understanding the mechanisms of statistical learning in autism has critical implications for language and cognitive interventions, emphasizing the importance of individualized support strategies.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":" ","pages":"2"},"PeriodicalIF":5.7,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12805773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820195","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":"Dim light at night disrupts the sleep-wake cycle and exacerbates abnormal EEG activity in Cntnap2 knockout mice: implications for autism spectrum disorders.","authors":"Yumeng Wang, Ketema N Paul, Gene D Block, Tom Deboer, Christopher S Colwell","doi":"10.1186/s13229-025-00689-7","DOIUrl":"10.1186/s13229-025-00689-7","url":null,"abstract":"<p><p>BACKGROUND: Epilepsy is a common comorbidity in individuals with autism spectrum disorders (ASDs). Many patients with epilepsy as well as ASD experience disruptions in their sleep-wake cycle and daily fluctuations in symptom severity. Chronic exposure to light at nighttime can disrupt sleep and circadian rhythms. Contactin associated protein-like 2 knockout (Cntnap2 KO) mice, a model of ASD and epilepsy, exhibit sleep and circadian disturbances and abnormal events in the electroencephalogram (EEG). Here, we investigated how chronic dim light at night (DLaN) exposure affects sleep architecture, EEG power spectra, and abnormal EEG events in Cntnap2 KO and wildtype (WT) mice. METHODS: Male and female Cntnap2 KO and WT mice were exposed to DLaN (5 lx) for 6 weeks. EEG recordings were collected and analyzed to assess sleep architecture, spectral power, and abnormal EEG events. A two-way repeated-measures analysis of variance (ANOVA) was used to evaluate the effects of DLaN across time and EEG frequencies, followed by Bonferroni-corrected post hoc tests where appropriate. RESULTS: DLaN exposure delayed wake onset and disrupted sleep patterns in a sex-dependent manner, with females being more affected. DLaN significantly increased slow-wave activity (SWA, 0.5–4 Hz) in both WT and KO mice, consistent with increased sleep pressure. Notably, DLaN markedly elevated the frequency of abnormal hypersynchronized EEG events in Cntnap2 KO mice and even induced such events in WT mice. Spectral analysis of abnormal EEG events revealed elevated theta power, suggesting hippocampal involvement. CONCLUSIONS: Chronic DLaN exposure disrupts sleep architecture in a sex-dependent fashion and increases the occurrence of abnormal EEG events in Cntnap2 KO mice. These findings highlight the potential risks of nighttime light exposure for individuals with ASD and epilepsy, underscoring the importance of managing light environments to improve sleep quality and neurological health.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"16 1","pages":"62"},"PeriodicalIF":5.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12713241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775045","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":"Atypical GNAO1 variants in severe childhood speech disorders: clinical, genetic, and molecular insights.","authors":"Yonika A Larasati, Moritz Thiel, Ainara Salazar-Villacorta, Alexey Koval, Manju A Kurian, Anne Koy, Angela T Morgan, Vladimir L Katanaev, Gonzalo P Solis","doi":"10.1186/s13229-025-00696-8","DOIUrl":"10.1186/s13229-025-00696-8","url":null,"abstract":"<p><strong>Background: </strong>The etiology of severe childhood speech disorders, including childhood apraxia of speech (CAS), is currently understood as genetically heterogeneous, with over 40 distinct monogenic conditions reported to date. Among them, the p.Thr327Arg variant in GNAO1, encoding the major neuronal G protein Gαo, was identified in one patient diagnosed with CAS and intellectual disability (ID). This presentation is exceptionally rare, as GNAO1 mutations are commonly associated with epilepsy, hyperkinetic movement disorders, and global developmental delay, often accompanied by ID.</p><p><strong>Methods: </strong>Here, we describe the clinical course of two patients with de novo heterozygous GNAO1 variants-p.Leu39_Gly40insVal and p.Thr327Lys-who exhibit severe speech disorder and ID as prominent symptoms. We also analyzed the biochemical and cellular properties of the mutant Gαo proteins alongside the previously reported p.Thr327Arg variant.</p><p><strong>Results: </strong>Molecular investigation of these three atypical Gαo mutants revealed aberrant GTP binding and hydrolysis, impaired association with RGS19, and a strong neomorphic gain of Ric8A interaction. Yet, all variants show normal plasma membrane localization despite poor Gβγ association, with p.Leu39_Gly40insVal exhibiting weak coupling to G protein-coupled receptors and p.Thr327Arg/Lys displaying near-normal coupling. Importantly, all three Gαo variants respond to Zn²⁺, supporting the potential therapeutic use of zinc supplementation for the patients.</p><p><strong>Limitations: </strong>These rare findings are based on a limited number of cases and require confirmation in additional patients to establish firmer genotype-phenotype correlations for GNAO1-related severe speech disorders.</p><p><strong>Conclusions: </strong>Our results broaden the clinical and mechanistic spectrum of GNAO1-related disorders, showing that severe speech disorders and ID can occur as defining features even in the absence of seizures or movement disorders. These findings highlight the importance of including GNAO1 in genetic testing for children with severe speech disorders.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":" ","pages":"1"},"PeriodicalIF":5.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12781765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743202","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":"Maternal rheumatoid arthritis and the risk of offspring autism spectrum disorder: two national birth cohorts and a meta-analysis.","authors":"Evora Hailin Zhu, Benjamin Hk Yip, Caroline Fyfe, Eugene Merzon, Arad Kodesh, Johan Askling, Abraham Reichenberg, Weiyao Yin, Stephen Z Levine, Sven Sandin","doi":"10.1186/s13229-025-00694-w","DOIUrl":"10.1186/s13229-025-00694-w","url":null,"abstract":"<p><p>BACKGROUND: Prenatal maternal rheumatoid arthritis (RA) is postulated to increase the risk of offspring with Autism Spectrum Disorder (ASD), yet findings of the association are inconsistent, potentially owing to small sample sizes and insufficient consideration of the timing of RA onset. This study aimed to examine the association between maternal RA, particularly its timing, and offspring ASD risk. METHODS: Two Israeli birth cohorts with national coverage and a meta-analysis were analyzed. Two harmonized birth cohorts of individuals born between 2003 and 2014 from Israeli Health Maintenance Organizations were followed up to 2021–05-01. Meta-analysis included all studies published up to 2023–06-07. Two exposures differentiated the timing of RA onset through maternal RA diagnosed before or after delivery. The association between maternal RA and the risk of offspring ASD was quantified by separate and pooled hazard ratios (HRs) from Cox proportional hazards regression with adjusted confounders. In the meta-analysis, the association was quantified using odds ratios (OR) fitted with random effects models with sensitivity analyses testing heterogeneity. RESULTS: Two Israeli birth cohorts included Cohort I (Population = 251,903; ASD = 1,939 [0.77%]) and Cohort II (Population = 309,696; ASD = 3,008 [0.97%]), contributing a total of 5.9 million person-years. Meta-analysis included 13 eligible studies (9 eligible estimates, population = 4,015,055, ASD = 45,124). Maternal RA before delivery increased the risk of offspring ASD (Cohort I HR = 1.55, 95% CI = 0.98–2.46; Cohort II HR = 1.83, 95% CI = 1.30–2.58; Combined I + II HR = 1.77, 95% CI = 1.45–2.17. Meta-analysis: OR = 1.57, 95% CI = 1.31–1.87). LIMITATIONS: Very few cases of seronegative RA compared to seropositive cases; RA subtype analysis was not feasible. It is important to acknowledge that the inclusion of the exposure “RA after delivery” also encompasses future RA information after the diagnosis of ASD, which may introduce biases. The association between RA drugs and offspring ASD risk has not been established due to a lack of data. CONCLUSIONS: Drawing on the strengths of two parallel birth cohorts from Israel and supported by meta-analysis, the current study indicates a modest but robust increase in the risk of ASD among offspring of mothers diagnosed with RA before delivery, but not when diagnosed only after delivery. This temporal specificity argues against shared genetic etiology and points toward maternal inflammatory status during pregnancy as a causal factor in offspring ASD risk.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"16 1","pages":"61"},"PeriodicalIF":5.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12679756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678222","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":"UBE3A stabilization of β-catenin preserves synaptic proteins essential for motor and cognitive functions in Angelman Syndrome.","authors":"Xin Yang, Yuwen-Alvin Huang, John Marshall","doi":"10.1186/s13229-025-00690-0","DOIUrl":"10.1186/s13229-025-00690-0","url":null,"abstract":"<p><p>BACKGROUND: Ubiquitin protein ligase E3A (UBE3A) regulates signaling pathways associated with autism spectrum disorders (ASDs). As an E3 ligase, UBE3A ubiquitinates and promotes the degradation of proteins crucial for regulating synaptic plasticity and learning. Loss-of-function mutations in UBE3A result in Angelman Syndrome, while gain-of-function or duplications contribute to ASDs and Dup15q Syndrome. METHODS: In this study, we investigated the effects of UBE3A loss on β-catenin stabilization in iPSC-derived neurons. We examined behavioral phenotypes in the Angelman Syndrome mouse model following lithium-induced inhibition of glycogen synthase kinase-3β (GSK3β). RESULTS: UBE3A insufficiency mimics Angelman Syndrome, leading to reduced β-catenin protein levels. Pharmacological inhibition of glycogen synthase kinase-3β (GSK3β) normalized both cytosolic and nuclear β-catenin levels and induced β-catenin-dependent expression of brain-derived neurotrophic factor (BDNF) and synaptic proteins. In the well-established UBE3A exon 2 deletion mouse model of Angelman syndrome, the pharmacological inhibition of GSK3β with lithium improved deficits in contextual fear and motor learning. UBE3A physically interacts with β-catenin, and inhibition of GSK3β decreased the excessive turnover of synaptic proteins in a β-catenin-dependent manner in UBE3A-depleted iNs. LIMITATIONS: The study is focused solely on lithium treatment for the exon 2 deletion mouse model. CONCLUSION: UBE3A regulates synaptic function by stabilizing β-catenin. GSK3β is overactive in AS, and precisely inhibiting GSK3β or stabilizing β-catenin represents a potential new therapeutic strategy for treating brain disorders, including Angelman Syndrome and autism spectrum disorders.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"16 1","pages":"60"},"PeriodicalIF":5.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12659537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636236","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":"The impact of camouflaging autistic traits on psychological and physiological stress: a co-twin control study.","authors":"Sabela Conde-Pumpido Zubizarreta, Johan Isaksson, Åshild Faresjö, Tomas Faresjö, Angel Carracedo, Montse Fernández Prieto, Sven Bölte, Karl Lundin Remnélius","doi":"10.1186/s13229-025-00695-9","DOIUrl":"10.1186/s13229-025-00695-9","url":null,"abstract":"<p><p>BACKGROUND: Camouflaging autistic traits is suggested to increase stress and the risk of autistic burnout. However, the relationship with psychological and biological markers of stress and the influence of familial factors on this relationship remain unclear. METHODS: In a neurodiverse twin sample (N = 315; 69 diagnosed with autism), we examined associations between camouflaging behaviors (operationalized as the discrepancy between the Autism Diagnostic Observation Schedule 2nd edition [ADOS-2] and the Autism Quotient [AQ]), rated stress-related symptoms, and biological long-term stress measured via hair cortisol concentration (HCC). Associations were analyzed across the full sample, accounting for age, sex, and HCC confounders, as well as within-twin pairs, implicitly adjusting for genetic and environmental confounding. RESULTS: Across individuals, camouflaging was associated with increased HCC, particularly in autistic and adult subsamples, while associations with stress-related symptoms were only evident in adults. Within-pair analyses revealed no associations in the full sample, suggesting familial confounding. Interestingly, in adjusted within-pair models in autistic and adult twin-pairs, camouflaging was linked to lower HCC. LIMITATIONS: Only the adult participants provided self-reports of autistic traits (AQ) and stress-related symptoms, while parent-reports were used for the younger participants. This difference in reporting sources may have reduced the accuracy of data for the younger subgroups in our sample. CONCLUSIONS: The findings indicate that camouflaging is associated with increased biological long-term stress at the population level but that familial factors may influence this relationship. Future research is needed to explore these complex dynamics and their implications for mental health and adaptive functioning in autistic individuals.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"16 1","pages":"59"},"PeriodicalIF":5.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12659362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636220","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":"Self-harm and suicidality experiences of autistic and non-autistic adults in midlife and old age.","authors":"Sophie Roper, Rebecca Charlton, Francesca Happé, Gavin R Stewart","doi":"10.1186/s13229-025-00693-x","DOIUrl":"10.1186/s13229-025-00693-x","url":null,"abstract":"<p><strong>Background: </strong>Suicide has been reported as a leading cause of premature death in autistic populations. Additionally, risk of suicidality is often found to increase with age in the general population. Despite this, suicidality has seldom been explored in autistic populations in midlife and old age. This study investigates the self-reported prevalence of self-harm and suicidality in autistic people in midlife and old age compared to an age- and gender-ratio comparable non-autistic group.</p><p><strong>Methods: </strong>In total, 388 participants (autistic n = 222, 44% men) aged 40-93 years (mean = 60.9 years) from the AgeWellAutism study completed questionnaires related to experiences of suicidal ideation, self-harming thoughts, deliberate self-harm, and suicidal self-harm. Group, gender and age differences were examined in chi-square and linear regression analyses.</p><p><strong>Results: </strong>The autistic group reported significantly higher rates of suicidal ideation, self-harming thoughts, deliberate self-harm, and suicidal self-harm than the non-autistic comparison group. When considering gender differences in the autistic group (but not the non-autistic group due to limited sample size), autistic women reported significantly higher rates of suicidal ideation and suicidal self-harm compared to autistic men; no other gender differences were found. When considering age differences, autistic people in old age were more likely to have had thoughts of self-harm, to have deliberately self-harmed, and to have experienced suicidal self-harm than autistic people in midlife.</p><p><strong>Limitations: </strong>The AgeWellAutism study is a cross-sectional convenience sample that relies on self-report. Survivor bias may also influence findings, as the study design would exclude those who have died by suicide, potentially leading to an underestimation of suicidality.</p><p><strong>Conclusions: </strong>Autistic adults may be particularly susceptible to experiences of self-harm and suicidality in midlife and old age, particularly autistic women. Additionally, autistic people in old age were also more likely to experience suicidality (including recent experiences) than autistic people in midlife. These findings highlight the urgent need for targeted suicide prevention strategies and mental health interventions for autistic adults in midlife and old age, particularly autistic women and older people.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":" ","pages":"58"},"PeriodicalIF":5.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12648868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604949","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":"Effects of Metformin on children with Fragile X Syndrome: a randomized, double-blind, placebo-controlled trial.","authors":"Yiting Zhu, Dongyun Li, Chunchun Hu, Yuxin Tian, Ping Lu, Randi J Hagerman, Xiu Xu, Qiong Xu","doi":"10.1186/s13229-025-00691-z","DOIUrl":"10.1186/s13229-025-00691-z","url":null,"abstract":"<p><strong>Background: </strong>Fragile X Syndrome (FXS) is the most prevalent inherited intellectual disability disorder linked to the X chromosome, and currently lacks an approved specific treatment. Preclinical and some clinical studies have suggested metformin may have therapeutic potential for FXS based on its mechanisms related to the disorder's pathophysiology.</p><p><strong>Methods: </strong>We conducted a 6-month, randomized, double-blind, placebo-controlled trial at the Children's Hospital of Fudan University. Thirty-four participants aged 2-16 years with genetically confirmed FXS were randomized 1:1 to receive weight-adjusted metformin (250-1000 mg/day) or placebo. Primary outcomes were changes in Aberrant Behavior Checklist (ABC); secondary outcomes included Griffiths Development Scale-Chinese (GDS-C), Autism Diagnostic Observation Program Second Edition (ADOS-2), Children's Sleep Habits Questionnaire (CSHQ), Repetitive Behavior Scale-Revised Chinese version (RBS-R), and Clinical Global Impression (CGI).</p><p><strong>Results: </strong>Among 34 randomized participants, 30 completed the trial (15 per group). Metformin demonstrated significant improvements in hyperactivity (ABC-Hyperactivity: -7.86 ± 6.97 vs. -0.80 ± 8.09, p = 0.016) and sleep disturbances (CSHQ-Total: -0.73 ± 5.14 vs. + 5.13 ± 6.85, p = 0.013), particularly bedtime resistance (p = 0.004). Total ABC score reductions favored metformin (-16.60 ± 15.31 vs. -4.00 ± 23.67) but did not reach significance (p = 0.095). No significant between-group differences were observed in cognitive, social, or repetitive behavior measures (GDS-C, ADOS-2, RBS-R). Adverse event rates were comparable, with IGF-1 reduced (6.7%, p = 1), transient appetite loss (13.3%, p = 0.483) and lactic acidosis (26.7%, p = 0.330) resolving spontaneously in metformin group.</p><p><strong>Limitation: </strong>This study was constrained by its modest sample size (n = 30), and absence of objective neurophysiological measures. The 6-month duration precluded assessment of long-term therapeutic effects.</p><p><strong>Conclusions: </strong>In this controlled trial, metformin did not significantly improve the primary outcome of ABC total score. However, significant improvements were observed in the hyperactivity subscale and key secondary outcomes, including sleep parameters, while maintaining a favorable safety profile. Although the primary endpoint was not met, these secondary findings support further investigation of metformin for targeted behavioral domains in individuals with FXS.</p><p><strong>Trial registration: </strong>This trial was prospectively registered on ClinicalTrials.gov (Registration No. NCT05120505, first posted November 03, 2021). The full protocol can be accessed at https://register.</p><p><strong>Clinicaltrials: </strong>gov/ .</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"16 1","pages":"57"},"PeriodicalIF":5.5,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12648774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604454","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":"Transdiagnostic similarities and distinctions in brain networks associated with autistic social impairments: a prospective cohort study.","authors":"Jennifer L Bruno, Julia R Plank, Samantha Leder, Evelyn M R Lake, Emily S Finn, Tamar Green","doi":"10.1186/s13229-025-00686-w","DOIUrl":"10.1186/s13229-025-00686-w","url":null,"abstract":"<p><strong>Background: </strong>Despite high rates of autism spectrum disorder (ASD), understanding of pathophysiology is limited. The RAS-mitogen-activated protein kinase (RAS-MAPK) pathway plays a crucial role in ASD and is altered in children with Noonan syndrome (NS). Children with NS offer a unique model to disentangle genetic and neurological underpinnings of ASD.</p><p><strong>Methods: </strong>This study aimed to examine functional brain network anatomy underlying social impairments in children with NS (n = 28, mean age = 8.24), and tested generalizability of models developed in a non-syndromic cohort enriched for ASD (Autism Brain Imaging Data Exchange (ABIDE), n = 352, mean age = 11.0). Connectome-based predictive modeling (CPM) was applied to fMRI data to predict the severity of autism symptoms, indexed by the Social Responsive Scale (SRS), in children with NS. Next, we tested if a model developed to predict autism symptoms in an autism-enriched sample of children without NS (ABIDE) could predict autism symptoms in children with NS.</p><p><strong>Results: </strong>Predicted SRS scores were significantly associated with observed SRS scores in NS (r_s = 0.43, p = 0.011). Application of the predictive model generated in the autism-enriched cohort (ABIDE) significantly predicted observed SRS scores in NS (r_s = 0.46, p = 0.018). Predictive brain networks in both NS and the non-syndromic cohorts included subcortical-cerebellar networks and visual processing networks.</p><p><strong>Limitations: </strong>The size of our NS cohort is small, given the rarity of NS. However, the significant cross-dataset comparison yielded in this study suggests that use of large publicly available datasets can be useful in contextualizing smaller and harder to collect datasets in rare genetic syndromes.</p><p><strong>Conclusions: </strong>The presence of shared brain networks suggests converging patterns of functional connectivity underlying autism symptoms across diagnoses. These findings point to potential overlap between non-syndromic autism and NS and highlight the value of human genetic models for studying ASD. Future work investigating RAS-MAPK pathway dysregulation may further elucidate its contribution to autism-related brain function.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"16 1","pages":"56"},"PeriodicalIF":5.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12628569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145549788","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":"Aberrant hippocampal gamma oscillations in a mouse model of fragile X syndrome: insights from in vitro slice models.","authors":"Evangelia Pollali, Daniel Frías Donaire, Miguel Del Ángel, Yunus Emre Demiray, Sara Enrile Lacalle, Jan-Oliver Hollnagel, Anil Annamneedi, Gürsel Çalışkan","doi":"10.1186/s13229-025-00687-9","DOIUrl":"10.1186/s13229-025-00687-9","url":null,"abstract":"<p><strong>Background: </strong>Fragile X syndrome (FXS) is the most common inherited intellectual disability, caused by the loss of fragile X mental retardation protein (FMRP), which regulates neuronal signaling and plasticity. FXS patients and Fmr1 knockout (KO) mice exhibit sensory hypersensitivity, hyperarousal, and hippocampus-dependent learning deficits. Dysregulated metabotropic glutamate receptor (mGluR) and muscarinic acetylcholine receptor (mAChR) signaling, along with reduced kainate receptor (KAR) function, have been implicated in FXS pathophysiology. Activation of these signaling pathways induce gamma-frequency network oscillations hippocampal slices in vitro. However, their specific contribution to aberrant gamma oscillations in FXS remains unclear.</p><p><strong>Methods: </strong>We recorded local field potential (LFP) gamma oscillations in vitro in hippocampal CA3 from wild-type (WT) and Fmr1 KO mice. Oscillations were induced pharmacologically using carbachol (CCh), the group I mGluR agonist dihydroxyphenylglycine (DHPG), or kainate (KA). In addition, we quantified synaptic protein expression of mAChR M1, mGluR1, mGluR5, GluK1, and GluK2-receptors involved in gamma oscillation generation under these conditions.</p><p><strong>Results: </strong>Fmr1 KO slices exhibited increased integrated gamma power (20-80 Hz) in response to DHPG and CCh, suggesting higher network synchronization through mGluR and mAChR pathways. In contrast, KA-induced oscillations showed reduced synchrony and gamma peak power, indicating disrupted network coordination. Aberrant spiking activity during both CCh- and KA-induced oscillations further supports impaired temporal coordination in Fmr1 KO mice. These physiological changes were only partially reflected by altered expression of the corresponding receptor proteins.</p><p><strong>Limitations: </strong>In the current study, we found aberrant gamma oscillation power in in vitro hippocampal slices of Fmr1 KO mice. It remains to be determined whether these oscillatory changes extend to pharmacologically induced gamma oscillations in cortical slice preparations in vitro.</p><p><strong>Conclusions: </strong>Our findings demonstrate that hippocampal gamma oscillations are differentially affected by distinct neuromodulatory pathways in Fmr1 KO mice. Enhanced responsiveness to cholinergic and mGluR activation and reduced coherence of KA-induced rhythms suggest that multiple dysregulated mechanisms contribute to gamma oscillopathies in FXS.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"16 1","pages":"55"},"PeriodicalIF":5.5,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12581432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431888","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}