Molecular Autism最新文献

{"title":"The neuroanatomical substrates of autism and ADHD and their link to putative genomic underpinnings.","authors":"Lisa M Berg, Caroline Gurr, Johanna Leyhausen, Hanna Seelemeyer, Anke Bletsch, Tim Schaefer, Charlotte M Pretzsch, Bethany Oakley, Eva Loth, Dorothea L Floris, Jan K Buitelaar, Christian F Beckmann, Tobias Banaschewski, Tony Charman, Emily J H Jones, Julian Tillmann, Chris H Chatham, Thomas Bourgeron, Declan G Murphy, Christine Ecker","doi":"10.1186/s13229-023-00568-z","DOIUrl":"10.1186/s13229-023-00568-z","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable across individuals and likely underpin distinct clinical phenotypes. To parse heterogeneity, it is essential to establish how the neurobiology of ASD is modulated by differences associated with co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to (1) investigate between-group differences in autistic individuals with and without co-occurring ADHD, and to (2) link these variances to putative genomic underpinnings.</p><p><strong>Methods: </strong>We examined differences in cortical thickness (CT) and surface area (SA) and their genomic associations in a sample of 533 individuals from the Longitudinal European Autism Project. Using a general linear model including main effects of autism and ADHD, and an ASD-by-ADHD interaction, we examined to which degree ADHD modulates the autism-related neuroanatomy. Further, leveraging the spatial gene expression data of the Allen Human Brain Atlas, we identified genes whose spatial expression patterns resemble our neuroimaging findings.</p><p><strong>Results: </strong>In addition to significant main effects for ASD and ADHD in fronto-temporal, limbic, and occipital regions, we observed a significant ASD-by-ADHD interaction in the left precentral gyrus and the right frontal gyrus for measures of CT and SA, respectively. Moreover, individuals with ASD + ADHD differed in CT to those without. Both main effects and the interaction were enriched for ASD-but not for ADHD-related genes.</p><p><strong>Limitations: </strong>Although we employed a multicenter design to overcome single-site recruitment limitations, our sample size of N = 25 individuals in the ADHD only group is relatively small compared to the other subgroups, which limits the generalizability of the results. Also, we assigned subjects into ADHD positive groupings according to the DSM-5 rating scale. While this is sufficient for obtaining a research diagnosis of ADHD, our approach did not take into account for how long the symptoms have been present, which is typically considered when assessing ADHD in the clinical setting.</p><p><strong>Conclusion: </strong>Thus, our findings suggest that the neuroanatomy of ASD is significantly modulated by ADHD, and that autistic individuals with co-occurring ADHD may have specific neuroanatomical underpinnings potentially mediated by atypical gene expression.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"36"},"PeriodicalIF":6.3,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41135918","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 rates of chronic physical health conditions across all organ systems in autistic adolescents and adults.","authors":"John H Ward, Elizabeth Weir, Carrie Allison, Simon Baron-Cohen","doi":"10.1186/s13229-023-00565-2","DOIUrl":"10.1186/s13229-023-00565-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The poorer physical health of autistic adults compared to non-autistic adults has been highlighted by several epidemiological studies. However, research has so far been limited to specific geographical areas and has primarily focused on young autistic individuals (aged 35 years and younger). Recent studies indicate a higher rate of mortality in autistic people, as well as poorer quality of self-reported healthcare interactions. This study aims to determine, first, whether autistic people experience greater levels of non-communicable health conditions and second, whether these are explained by differences in demographics (i.e. sex, country of residence, ethnicity, education level), alcohol use, smoking, body mass index (BMI), or family history of medical conditions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Method: &lt;/strong&gt;We employed a cross-sectional, convenience-sampling study via an anonymous, online survey of autistic and non-autistic adults (n = 2305, mean age = 41.6, 65.9% female, 49% autistic). The survey asked participants to self-report information about their demographics, autism diagnosis, diet, exercise, sleep, sexual health, substance use, personal medical history, and family medical history (for all first-degree, biological relatives). Binomial logistic regression across four iterative models of increasing complexity was applied to assess rates of physical health conditions. The Benjamini-Hochberg correction was used to account for multiple testing, and only physical health conditions that achieved at least 1% endorsement within the overall sample (n &gt; 22) were included in the analysis to reduce risk of Type I errors. We also used novel network analysis methods to test whether there are increased levels of multimorbidity between autistic and non-autistic people.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;There were significantly elevated rates of non-communicable conditions across all organ systems in autistic people, including gastrointestinal, neurological, endocrine, visual, ear/nose/throat, skin, liver and kidney, and haematological conditions. We confirmed previous findings by showing highly significant differences in rates of neurological and gastrointestinal symptoms (p &lt; 0.0001). In addition, we established in the largest sample to date that Ehler-Danlos Syndrome (EDS) was more likely to occur among autistic females compared to non-autistic females. Finally, we found a higher prevalence of Coeliac's disease among autistic individuals compared to non-autistic individuals after controlling for sex, ethnicity, country of residence, alcohol use, smoking, and BMI, but these results became non-significant after accounting for family history.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Limitations: &lt;/strong&gt;Our study is biased towards females, white individuals, highly educated people, and UK residents, likely due to sampling biases. Our self-report study design may also exclude those who lack access to computers, or those with intellectual disability. Our network an","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"35"},"PeriodicalIF":6.2,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134747","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":"Cortex-restricted deletion of Foxp1 impairs barrel formation and induces aberrant tactile responses in a mouse model of autism.","authors":"Xue Li, Shishuai Hao, Shimin Zou, Xiaomeng Tu, Weixi Kong, Tian Jiang, Jie-Guang Chen","doi":"10.1186/s13229-023-00567-0","DOIUrl":"10.1186/s13229-023-00567-0","url":null,"abstract":"<p><strong>Background: </strong>Many children and young people with autism spectrum disorder (ASD) display touch defensiveness or avoidance (hypersensitivity), or engage in sensory seeking by touching people or objects (hyposensitivity). Abnormal sensory responses have also been noticed in mice lacking ASD-associated genes. Tactile sensory information is normally processed by the somatosensory system that travels along the thalamus to the primary somatosensory cortex. The neurobiology behind tactile sensory abnormalities, however, is not fully understood.</p><p><strong>Methods: </strong>We employed cortex-specific Foxp1 knockout (Foxp1-cKO) mice as a model of autism in this study. Tactile sensory deficits were measured by the adhesive removal test. The mice's behavior and neural activity were further evaluated by the whisker nuisance test and c-Fos immunofluorescence, respectively. We also studied the dendritic spines and barrel formation in the primary somatosensory cortex by Golgi staining and immunofluorescence.</p><p><strong>Results: </strong>Foxp1-cKO mice had a deferred response to the tactile environment. However, the mice exhibited avoidance behavior and hyper-reaction following repeated whisker stimulation, similar to a fight-or-flight response. In contrast to the wild-type, c-Fos was activated in the basolateral amygdala but not in layer IV of the primary somatosensory cortex of the cKO mice. Moreover, Foxp1 deficiency in cortical neurons altered the dendrite development, reduced the number of dendritic spines, and disrupted barrel formation in the somatosensory cortex, suggesting impaired somatosensory processing may underlie the aberrant tactile responses.</p><p><strong>Limitations: </strong>It is still unclear how the defective thalamocortical connection gives rise to the hyper-reactive response. Future experiments with electrophysiological recording are needed to analyze the role of thalamo-cortical-amygdala circuits in the disinhibiting amygdala and enhanced fearful responses in the mouse model of autism.</p><p><strong>Conclusions: </strong>Foxp1-cKO mice have tactile sensory deficits while exhibit hyper-reactivity, which may represent fearful and emotional responses controlled by the amygdala. This study presents anatomical evidence for reduced thalamocortical connectivity in a genetic mouse model of ASD and demonstrates that the cerebral cortex can be the origin of atypical sensory behaviors.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"34"},"PeriodicalIF":6.2,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10494400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10211644","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":"Autistic adults benefit from and enjoy learning via social interaction as much as neurotypical adults do.","authors":"S De Felice, A Hatilova, F Trojan, I Tsui, Antonia F de C Hamilton","doi":"10.1186/s13229-023-00561-6","DOIUrl":"10.1186/s13229-023-00561-6","url":null,"abstract":"<p><strong>Background: </strong>Autistic people show poor processing of social signals (i.e. about the social world). But how do they learn via social interaction?</p><p><strong>Methods: </strong>68 neurotypical adults and 60 autistic adults learned about obscure items (e.g. exotic animals) over Zoom (i) in a live video-call with the teacher, (ii) from a recorded learner-teacher interaction video and (iii) from a recorded teacher-alone video. Data were analysed via analysis of variance and multi-level regression models.</p><p><strong>Results: </strong>Live teaching provided the most optimal learning condition, with no difference between groups. Enjoyment was the strongest predictor of learning: both groups enjoyed the live interaction significantly more than other condition and reported similar anxiety levels across conditions.</p><p><strong>Limitations: </strong>Some of the autistic participants were self-diagnosed-however, further analysis where these participants were excluded showed the same results. Recruiting participants over online platforms may have introduced bias in our sample. Future work should investigate learning in social contexts via diverse sources (e.g. schools).</p><p><strong>Conclusions: </strong>These findings advocate for a distinction between learning about the social versus learning via the social: cognitive models of autism should be revisited to consider social interaction not just as a puzzle to decode but rather a medium through which people, including neuro-diverse groups, learn about the world around them. Trial registration Part of this work has been pre-registered before data collection https://doi.org/10.17605/OSF.IO/5PGA3.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"33"},"PeriodicalIF":6.2,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10481576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10242488","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":"Linking functional and structural brain organisation with behaviour in autism: a multimodal EU-AIMS Longitudinal European Autism Project (LEAP) study.","authors":"Lennart M Oblong, Alberto Llera, Ting Mei, Koen Haak, Christina Isakoglou, Dorothea L Floris, Sarah Durston, Carolin Moessnang, Tobias Banaschewski, Simon Baron-Cohen, Eva Loth, Flavio Dell'Acqua, Tony Charman, Declan G M Murphy, Christine Ecker, Jan K Buitelaar, Christian F Beckmann, Natalie J Forde","doi":"10.1186/s13229-023-00564-3","DOIUrl":"10.1186/s13229-023-00564-3","url":null,"abstract":"<p><p>Neuroimaging analyses of brain structure and function in autism have typically been conducted in isolation, missing the sensitivity gains of linking data across modalities. Here we focus on the integration of structural and functional organisational properties of brain regions. We aim to identify novel brain-organisation phenotypes of autism. We utilised multimodal MRI (T1-, diffusion-weighted and resting state functional), behavioural and clinical data from the EU AIMS Longitudinal European Autism Project (LEAP) from autistic (n = 206) and non-autistic (n = 196) participants. Of these, 97 had data from 2 timepoints resulting in a total scan number of 466. Grey matter density maps, probabilistic tractography connectivity matrices and connectopic maps were extracted from respective MRI modalities and were then integrated with Linked Independent Component Analysis. Linear mixed-effects models were used to evaluate the relationship between components and group while accounting for covariates and non-independence of participants with longitudinal data. Additional models were run to investigate associations with dimensional measures of behaviour. We identified one component that differed significantly between groups (coefficient = 0.33, p_adj = 0.02). This was driven (99%) by variance of the right fusiform gyrus connectopic map 2. While there were multiple nominal (uncorrected p < 0.05) associations with behavioural measures, none were significant following multiple comparison correction. Our analysis considered the relative contributions of both structural and functional brain phenotypes simultaneously, finding that functional phenotypes drive associations with autism. These findings expanded on previous unimodal studies by revealing the topographic organisation of functional connectivity patterns specific to autism and warrant further investigation.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"32"},"PeriodicalIF":6.2,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10472578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10145765","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":"Examining the latent structure and correlates of sensory reactivity in autism: a multi-site integrative data analysis by the autism sensory research consortium.","authors":"Zachary J Williams, Roseann Schaaf, Karla K Ausderau, Grace T Baranek, D Jonah Barrett, Carissa J Cascio, Rachel L Dumont, Ekomobong E Eyoh, Michelle D Failla, Jacob I Feldman, Jennifer H Foss-Feig, Heather L Green, Shulamite A Green, Jason L He, Elizabeth A Kaplan-Kahn, Bahar Keçeli-Kaysılı, Keren MacLennan, Zoe Mailloux, Elysa J Marco, Lisa E Mash, Elizabeth P McKernan, Sophie Molholm, Stewart H Mostofsky, Nicolaas A J Puts, Caroline E Robertson, Natalie Russo, Nicole Shea, John Sideris, James S Sutcliffe, Teresa Tavassoli, Mark T Wallace, Ericka L Wodka, Tiffany G Woynaroski","doi":"10.1186/s13229-023-00563-4","DOIUrl":"10.1186/s13229-023-00563-4","url":null,"abstract":"<p><strong>Background: </strong>Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these \"supra-modal\" traits in the autistic population.</p><p><strong>Methods: </strong>Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a \"general response pattern\" factor for each supra-modal construct and determine the added value of \"modality-specific response pattern\" scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs.</p><p><strong>Results: </strong>All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ω_H = .800) but not a supra-modal HYPO construct (ω_H = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ω_H = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations).</p><p><strong>Limitations: </strong>Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many \"real-world\" sensory experiences.</p><p><strong>Conclusion: </strong>Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"31"},"PeriodicalIF":6.2,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10498701","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":"Sex-specific and sex-independent steroid-related biomarkers in early second trimester maternal serum associated with autism.","authors":"Deborah A Bilder, Whitney Worsham, Scott Sullivan, M Sean Esplin, Paul Burghardt, Alison Fraser, Amanda V Bakian","doi":"10.1186/s13229-023-00562-5","DOIUrl":"10.1186/s13229-023-00562-5","url":null,"abstract":"<p><strong>Background: </strong>Prenatal exposure to maternal metabolic conditions associated with inflammation and steroid dysregulation has previously been linked to increased autism risk. Steroid-related maternal serum biomarkers have also provided insight into the in utero steroid environment for offspring who develop autism.</p><p><strong>Objective: </strong>This study examines the link between autism among offspring and early second trimester maternal steroid-related serum biomarkers from pregnancies enriched for prenatal metabolic syndrome (PNMS) exposure.</p><p><strong>Study design: </strong>Early second trimester maternal steroid-related serum biomarkers (i.e., estradiol, free testosterone, total testosterone, and sex hormone binding globulin) were compared between pregnancies corresponding to offspring with (N = 68) and without (N = 68) autism. Multiple logistic regression analyses were stratified by sex and gestational duration. One-way ANCOVA with post hoc tests was performed for groups defined by autism status and PNMS exposure.</p><p><strong>Results: </strong>Increased estradiol was significantly associated with autism only in males (AOR = 1.13 per 100 pg/ml, 95% CI 1.01-1.27, p = 0.036) and only term pregnancies (AOR = 1.17 per 100 pg/ml, 95% CI 1.04-1.32, p = 0.010). Autism status was significantly associated with decreased sex hormone binding globulin (AOR = 0.65 per 50 nmol/L, 95% CI 0.55-0.78, p < 0.001) overall and when stratified by sex and term pregnancy status. The inverse association between sex hormone binding globulin and autism was independent of PNMS exposure.</p><p><strong>Limitations: </strong>The relative racial and ethnic homogeneity of Utah's population limits the generalizability of study results. Although significant differences by autism status were identified in concentrations of sex hormone binding globulin overall and of estradiol in participant subgroups, differences by PNMS exposure failed to reach statistical significance, which may reflect insufficient statistical power.</p><p><strong>Conclusion: </strong>Both elevated maternal serum estradiol in males only and low maternal serum sex hormone binding globulin in both sexes are associated with increased autism risk. Further investigation is merited to identify how steroid, metabolic, and inflammatory processes can interact to influence neurodevelopment in early second trimester.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"30"},"PeriodicalIF":6.2,"publicationDate":"2023-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10422808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9988892","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":"Knockout of Tmlhe in mice is not associated with autism spectrum disorder phenotypes or motor dysfunction despite low carnitine levels.","authors":"Edgars Liepinsh, Baiba Svalbe, Gundega Stelfa, Solveiga Grinberga, Liga Zvejniece, Helgi B Schiöth, Maija Dambrova","doi":"10.1186/s13229-023-00560-7","DOIUrl":"10.1186/s13229-023-00560-7","url":null,"abstract":"<p><p>Deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene was identified in probands with autism spectrum disorder (ASD). TMLHE encodes the first enzyme in carnitine biosynthesis, N6-trimethyllysine dioxygenase (TMLD). Researchers have suggested that carnitine depletion could be important for the development of ASD and cognitive, locomotor and social dysfunctions, but previous findings have been inconclusive regarding the specific role of endogenous carnitine. We developed a mouse knockout model with constitutive TMLD enzyme inactivation that exhibited a significant decrease in the carnitine by more than 90% compared to wild-type (WT) mice. However, we did not observe any significant social, cognitive, or repetitive-behavior changes associated with ASD in the knockout mice; muscle strength and coordination were also not affected. In addition, the life expectancy of knockout mice was similar to that of WT mice. In conclusion, knockout of Tmlh in mice does not induce an ASD phenotype or motor dysfunction despite extremely low carnitine and gamma-butyrobetaine concentrations. Moreover, inactivation of TMLD does not induce a phenotype similar to previously described primary carnitine deficiency; indeed, our results showed that low levels of carnitine sustained adequate energy production, muscle function and social behavior in mice.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"29"},"PeriodicalIF":6.2,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9993763","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":"Shank3 deletion in PV neurons is associated with abnormal behaviors and neuronal functions that are rescued by increasing GABAergic signaling.","authors":"Jessica Pagano,&nbsp;Silvia Landi,&nbsp;Alessia Stefanoni,&nbsp;Gabriele Nardi,&nbsp;Marica Albanesi,&nbsp;Helen F Bauer,&nbsp;Enrico Pracucci,&nbsp;Michael Schön,&nbsp;Gian Michele Ratto,&nbsp;Tobias M Boeckers,&nbsp;Carlo Sala,&nbsp;Chiara Verpelli","doi":"10.1186/s13229-023-00557-2","DOIUrl":"https://doi.org/10.1186/s13229-023-00557-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic-like behaviors and is primarily caused by haploinsufficiency of SHANK3 gene. Currently, there is no specific treatment for PMS, highlighting the need for a better understanding of SHANK3 functions and the underlying pathophysiological mechanisms in the brain. We hypothesize that SHANK3 haploinsufficiency may lead to alterations in the inhibitory system, which could be linked to the excitatory/inhibitory imbalance observed in models of autism spectrum disorder (ASD). Investigation of these neuropathological features may shed light on the pathogenesis of PMS and potential therapeutic interventions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We recorded local field potentials and visual evoked responses in the visual cortex of Shank3∆11&lt;sup&gt;-/-&lt;/sup&gt; mice. Then, to understand the impact of Shank3 in inhibitory neurons, we generated Pv-cre&lt;sup&gt;+/-&lt;/sup&gt; Shank3&lt;sup&gt;Fl/Wt&lt;/sup&gt; conditional mice, in which Shank3 was deleted in parvalbumin-positive neurons. We characterized the phenotype of this murine model and we compared this phenotype before and after ganaxolone administration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We found, in the primary visual cortex, an alteration of the gain control of Shank3 KO compared with Wt mice, indicating a deficit of inhibition on pyramidal neurons. This alteration was rescued after the potentiation of GABA&lt;sub&gt;A&lt;/sub&gt; receptor activity by Midazolam. Behavioral analysis showed an impairment in grooming, memory, and motor coordination of Pv-cre&lt;sup&gt;+/-&lt;/sup&gt; Shank3&lt;sup&gt;Fl/Wt&lt;/sup&gt; compared with Pv-cre&lt;sup&gt;+/-&lt;/sup&gt; Shank3&lt;sup&gt;Wt/Wt&lt;/sup&gt; mice. These deficits were rescued with ganaxolone, a positive modulator of GABA&lt;sub&gt;A&lt;/sub&gt; receptors. Furthermore, we demonstrated that treatment with ganaxolone also ameliorated evocative memory deficits and repetitive behavior of Shank3 KO mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Limitations: &lt;/strong&gt;Despite the significant findings of our study, some limitations remain. Firstly, the neurobiological mechanisms underlying the link between Shank3 deletion in PV neurons and behavioral alterations need further investigation. Additionally, the impact of Shank3 on other classes of inhibitory neurons requires further exploration. Finally, the pharmacological activity of ganaxolone needs further characterization to improve our understanding of its potential therapeutic effects.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our study provides evidence that Shank3 deletion leads to an alteration in inhibitory feedback on cortical pyramidal neurons, resulting in cortical hyperexcitability and ASD-like behavioral problems. Specifically, cell type-specific deletion of Shank3 in PV neurons was associated with these behavioral deficits. Our findings suggest that ganaxolone may be a potential pharmacological approach for treating PMS, as it was able to rescue the behavioral defi","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"28"},"PeriodicalIF":6.2,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10394945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9987324","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":"Personalized estimates of brain cortical structural variability in individuals with Autism spectrum disorder: the predictor of brain age and neurobiology relevance.","authors":"Yingying Xie,&nbsp;Jie Sun,&nbsp;Weiqi Man,&nbsp;Zhang Zhang,&nbsp;Ningnannan Zhang","doi":"10.1186/s13229-023-00558-1","DOIUrl":"https://doi.org/10.1186/s13229-023-00558-1","url":null,"abstract":"<p><strong>Background: </strong>Autism spectrum disorder (ASD) is a heritable condition related to brain development that affects a person's perception and socialization with others. Here, we examined variability in the brain morphology in ASD children and adolescent individuals at the level of brain cortical structural profiles and the level of each brain regional measure.</p><p><strong>Methods: </strong>We selected brain structural MRI data in 600 ASDs and 729 normal controls (NCs) from Autism Brain Imaging Data Exchange (ABIDE). The personalized estimate of similarity between gray matter volume (GMV) profiles of an individual to that of others in the same group was assessed by using the person-based similarity index (PBSI). Regional contributions to PBSI score were utilized for brain age gap estimation (BrainAGE) prediction model establishment, including support vector regression (SVR), relevance vector regression (RVR), and Gaussian process regression (GPR). The association between BrainAGE prediction in ASD and clinical performance was investigated. We further explored the related inter-regional profiles of gene expression from the Allen Human Brain Atlas with variability differences in the brain morphology between groups.</p><p><strong>Results: </strong>The PBSI score of GMV was negatively related to age regardless of the sample group, and the PBSI score was significantly lower in ASDs than in NCs. The regional contributions to the PBSI score of 126 brain regions in ASDs showed significant differences compared to NCs. RVR model achieved the best performance for predicting brain age. Higher inter-individual brain morphology variability was related to increased brain age, specific to communication symptoms. A total of 430 genes belonging to various pathways were identified as associated with brain cortical morphometric variation. The pathways, including short-term memory, regulation of system process, and regulation of nervous system process, were dominated mainly by gene sets for manno midbrain neurotypes.</p><p><strong>Limitations: </strong>There is a sample mismatch between the gene expression data and brain imaging data from ABIDE. A larger sample size can contribute to the model training of BrainAGE and the validation of the results.</p><p><strong>Conclusions: </strong>ASD has personalized heterogeneity brain morphology. The brain age gap estimation and transcription-neuroimaging associations derived from this trait are replenished in an additional direction to boost the understanding of the ASD brain.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":"14 1","pages":"27"},"PeriodicalIF":6.2,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9916079","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}