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Bioscience Trends Jun 2024The brain-gut axis intricately links gut microbiota (GM) dysbiosis to the development or worsening of autism spectrum disorder (ASD). However, the precise GM composition...
The brain-gut axis intricately links gut microbiota (GM) dysbiosis to the development or worsening of autism spectrum disorder (ASD). However, the precise GM composition in ASD and the effectiveness of probiotics are unclear. To address this, we performed a thorough meta-analysis of 28 studies spanning PubMed, PsycINFO, Web of Science, Scopus, and MEDLINE, involving 1,256 children with ASD and 1042 neurotypical children, up to February 2024. Using Revman 5.3, we analyzed the relative abundance of 8 phyla and 64 genera. While individuals with ASD did not exhibit significant differences in included phyla, they exhibited elevated levels of Parabacteroides, Anaerostipes, Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Lachnoclostridium, Catenibacterium, and Collinsella along with reduced percentages of Barnesiella, Odoribacter, Paraprevotella, Blautia, Turicibacter, Lachnospira, Pseudomonas, Parasutterella, Haemophilus, and Bifidobacterium. Notably, discrepancies in Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Catenibacterium, Odoribacter, and Bifidobacterium persisted even upon systematic exclusion of individual studies. Consequently, the GM of individuals with ASD demonstrates an imbalance, with potential increases or decreases in both beneficial and harmful bacteria. Therefore, personalized probiotic interventions tailored to ASD specifics are imperative, rather than a one-size-fits-all approach.
PubMed: 38897955
DOI: 10.5582/bst.2024.01123 -
BMJ Paediatrics Open Jun 2024The UK National Health Service (NHS) Long Term Plan aims to reduce waiting times for childhood autism diagnostic assessment and improve parent and child satisfaction....
BACKGROUND
The UK National Health Service (NHS) Long Term Plan aims to reduce waiting times for childhood autism diagnostic assessment and improve parent and child satisfaction. This empirical research investigated current childhood diagnostic practice provision, and changes made by teams to address challenges faced.
METHODS
Data were collected using an online semi-structured research questionnaire. UK childhood autism diagnostic assessment services (for children aged 1-18 years) were invited to participate through multidisciplinary clinical networks, special interest groups and professionals mailing lists. The study was on the National Institute for Health Research Clinical Research Network portfolio.
RESULTS
128 clinicians from diverse NHS services responded including: 10 (8%) integrated services, 46 (36%) Child and Adolescent Mental Health Services (CAMHS) and 72 (56%) paediatric services. A minority of services (23, 17.9%) reported always meeting the National Institute for Health and Care Excellence guidance for assessment. Referrals rose 115% between 2015 and 2019. Clinicians described increased child and family complexity compared with previously; children had more co-occurring physical, mental health and neurodevelopmental conditions and there were more frequent family health problems and safeguarding concerns. Most services (97, 75.8%) reported recent funding stayed constant/decreased. Incomplete multidisciplinary teams (MDTs) were frequently reported; a minority of services reported increased availability of professionals, and some experienced reductions in key professionals. Many teams were unable to undertake assessments or make recommendations for associated neurodevelopmental and co-existing conditions. Teams described improvement strategies implemented (eg, adapting professionals' roles, supporting parents).
CONCLUSIONS
Most UK autism paediatric and CAMHS diagnostic teams experience significant challenges affecting the assessment of children with possible autism, and recommendations regarding treatment/intervention. Where CAMHS or paediatric services work in isolation, there are often competency gaps in MDTs and ability to deliver full neurodevelopmental and mental health assessments. Teams identified service improvement strategies; however, investment in MDT expertise is required to enable services to implement changes to meet the needs of children and families.
Topics: Humans; United Kingdom; Child; Child, Preschool; Adolescent; Autistic Disorder; Infant; Male; Female; Surveys and Questionnaires; Child Health Services; State Medicine; Referral and Consultation; Health Care Surveys
PubMed: 38897620
DOI: 10.1136/bmjpo-2024-002496 -
Brain, Behavior, and Immunity Jun 2024Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and...
Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and mental illnesses. Using a viral-like MIA model that is based on prenatal poly(I:C) exposure in mice, we have recently identified the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network and inflammatory profiles even under conditions of genetic homogeneity and identical MIA. Here, we tested the hypothesis that the intrauterine positions of fetuses, which are known to shape individual variability in litter-bearing mammals through variations in fetal hormone exposure, may contribute to the variable outcomes of MIA in mice. MIA was induced by maternal administration of poly(I:C) on gestation day 12 in C57BL/6N mice. Determining intrauterine positions using delivery by Cesarean section (C-section), we found that MIA-exposed offspring developing between female fetuses only (0M-MIA offspring) displayed significant deficits in sociability and sensorimotor gating at adult age, whereas MIA-exposed offspring developing between one or two males in utero (1/2M-MIA offspring) did not show the same deficits. These intrauterine position effects similarly emerged in male and female offspring. Furthermore, while MIA elevated fetal brain levels of pro- and anti-inflammatory cytokines independently of the precise intrauterine position and sex of adjacent fetuses during the acute phase, fetal brain levels of TNF-α remained elevated in 0M-MIA but not 1/2M-MIA offspring until the post-acute phase in late gestation. As expected, 1/2M offspring generally showed higher testosterone levels in the fetal brain during late gestation as compared to 0M offspring, confirming the transfer of testosterone from male fetuses to adjacent male or female fetuses. Taken together, our findings identify a novel source of within-litter variability contributing to heterogeneous outcomes of short- and long-term effects in a mouse model of MIA. In broader context, our findings highlight that individual differences in fetal exposure to hormonal and inflammatory signals may be a perinatal factor that shapes risk and resilience to MIA.
PubMed: 38897330
DOI: 10.1016/j.bbi.2024.06.015 -
Stem Cell Research Jun 2024Autism spectrum disorder (ASD) is a complex developmental disorder characterized by challenges with social interactions and restricted/repetitive behaviors. Here, we...
Generation of nine induced pluripotent stem cell lines from six young children with autism spectrum disorder and three matched control subjects from the Qatari population.
Autism spectrum disorder (ASD) is a complex developmental disorder characterized by challenges with social interactions and restricted/repetitive behaviors. Here, we recruited nine Qatari children of Arab ethnicity (males, aged 2-4 years), including six ASD subjects (n = 3 mild-to-moderate ASD and n = 3 severe ASD) and three control subjects. We generated induced pluripotent stem cell (iPSC) lines from PBMC samples of these subjects using non-integrating Sendai viral vectors. These iPSC lines were fully characterized and exhibited pluripotency characteristics, normal karyotypes, and trilineage differentiation potential. These iPSC lines provide valuable cell models for understanding ASD pathophysiology and developing new therapeutics for ASD.
PubMed: 38896970
DOI: 10.1016/j.scr.2024.103470 -
Frontiers in Veterinary Science 2024Given the rising interest in complementary therapeutic strategies for autism spectrum disorder (ASD), this research aims to provide a comprehensive analysis of the...
BACKGROUND
Given the rising interest in complementary therapeutic strategies for autism spectrum disorder (ASD), this research aims to provide a comprehensive analysis of the impact of animal-assisted activities and therapies (AAAT) on various ASD symptoms.
METHODS
A meticulous search of databases, including Scopus and PubMed, was conducted to gather relevant research on AAAT for ASD. This process led to the selection of 45 studies encompassing 1,212 participants. The chosen studies were then subjected to a meta-analysis to evaluate the efficacy of AAAT in alleviating core ASD symptoms.
RESULTS
The meta-analysis revealed significant improvements in several core ASD symptoms due to AAAT. Notably, there were improvements in social communication (MD = -4.96, 95% CI [-7.49, -2.44]), irritability (MD = -2.38, 95% CI [-4.06, -0.71]), hyperactivity (MD = -4.03, 95% CI [-6.17, -1.89]), and different word usage skills (MD = 20.48, 95% CI [7.41, 33.55]). However, social awareness (MD = -1.63, 95% CI [-4.07, 0.81]), social cognition (MD = -3.60, 95% CI [-9.36, 2.17]), social mannerisms (MD = -0.73, 95% CI [-2.55, 1.09]), social motivation (MD = -1.21, 95% CI [-2.56, 0.13]), lethargy (MD = -1.12, 95% CI [-3.92, 1.68]), and stereotypical behaviors (MD = -0.23, 95% CI [-1.27, 0.80]) did not significantly improve.
CONCLUSION
The study demonstrates the potential of AAAT in improving certain core symptoms of ASD, such as social communication, irritability, hyperactivity, and word usage skills. However, the effectiveness of AAAT in other ASD symptom domains remains uncertain. The research is limited by the absence of long-term follow-up data and a high risk of bias in existing studies. Therefore, while the findings indicate the promise of AAAT in specific areas, caution is advised in generalizing its efficacy across all ASD symptoms.
PubMed: 38895710
DOI: 10.3389/fvets.2024.1403527 -
BioRxiv : the Preprint Server For... Jun 2024It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent...
UNLABELLED
It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified loss-of-function (dnLoF) mutations in the as a strong risk factor for ASD. Previous research has shown that ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of , as in the +/- mice, displayed hyperactivity, increased anxiety, and motor coordination impairments. Additionally, hippocampal-dependent learning and memory was affected, including working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, LoF produces autistic-like behaviors that are similar to human cases of ASD. These findings further support a role for dnLoF mutations in ASD and suggest +/- as a suitable model for ASD research.
SUMMARY STATEMENT
Autism spectrum disorder represents a growing patient population. Loss of one copy of the gene provides a promising mouse model that reproduces autistic-like behaviors for research and therapeutic testing.
PubMed: 38895491
DOI: 10.1101/2024.06.03.597158 -
BioRxiv : the Preprint Server For... Jun 2024Cortical development is a tightly controlled process and any deviation during development may increase the susceptibility to neurodevelopmental disorders, such as autism...
Cortical development is a tightly controlled process and any deviation during development may increase the susceptibility to neurodevelopmental disorders, such as autism spectrum disorders (ASD). Numerous studies identified mutations in , a transcription factor enriched in the neocortex, as causal for ASD and FOXP1 syndrome. Our group has shown that deletion in the mouse cortex leads to overall reduced cortex thickness, alterations in cortical lamination, and changes in the relative thickness of cortical layers. However, the developmental and cell type-specific mechanisms underlying these changes remained unclear. This work characterizes the developmental requirement of neocortical at key embryonic and perinatal ages using a conditional knock-out of . We find that deletion results in accelerated pseudo-age during early neurogenesis, increased cell cycle exit during late neurogenesis, altered gene expression and chromatin accessibility, and selective migration deficits in a subset of upper-layer neurons. These data explain the postnatal differences observed in cortical layers and relative cortical thickness. We also highlight genes regulated by FOXP1 and their enrichment with high-confidence ASD or synaptic genes. Together, these results underscore a network of neurodevelopmental disorder-related genes that may serve as potential modulatory targets for postnatal modification relevant to ASD and FOXP1 syndrome.
PubMed: 38895440
DOI: 10.1101/2024.06.08.598089 -
BioRxiv : the Preprint Server For... Jun 2024Tuberous sclerosis complex (TSC), an inherited neurodevelopmental (ND) disorder with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is...
Tuberous sclerosis complex (TSC), an inherited neurodevelopmental (ND) disorder with frequent manifestations of epilepsy and autism spectrum disorder (ASD). TSC is caused by mutations in or tumor suppressor genes, with encoded proteins hamartin/TSC1 and tuberin/TSC2 forming a functional complex inhibiting mechanistic target of rapamycin complex-1 (mTORC1) signaling, leading to FDA-approved allosteric mTORC1-selective rapamycin analogs for TSC tumors. Rapalogs are effective for TSC-associated hamartomas, however, they are not effective for treating ND manifestations. mTORC1 signaling plays an essential role in protein synthesis through mTORC1-eIF4F and MNK-eIF4E-mediated mRNA translation. Further, the effects on mRNA translation by specific mTORC1 and MNK inhibitors such as RMC-6272 and eFT-508 in TSC have never been explored. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we have examined mRNA translation upon loss of . Our results reveal dysregulated translation in -Null NPCs, which significantly overlap with the translatome from -Null NPCs, which we reported recently. Most notably, numerous non-monogenic ASD-NDD- and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, including protein truncating, or damaging missense variants, were translationally suppressed in -Null NPCs, and their translation were reversed upon RMC-6272 or eFT-508 treatment. Our study here establishes the importance of mTORC1-eIF4F and MNK-eIF4E-mediated mRNA translation in TSC, ASD and other neurodevelopmental disorders and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD.
PubMed: 38895292
DOI: 10.1101/2024.06.04.597393 -
BioRxiv : the Preprint Server For... Jun 2024Autism spectrum disorder (ASD) presents with diverse cognitive and behavioral abnormalities beginning during early development. Although the neural circuit mechanisms...
Autism spectrum disorder (ASD) presents with diverse cognitive and behavioral abnormalities beginning during early development. Although the neural circuit mechanisms remain unclear, recent work suggests pathology in cortical inhibitory interneurons (INs) plays a crucial role. However, we lack fundamental information regarding changes in the physiology of synapses to and from INs in ASD. Here, we used transgenic mice to conditionally knockout one copy of the high confidence ASD risk gene from the progenitors of parvalbumin-expressing fast-spiking (PV-FS) INs and somatostatin-expressing non-fast-spiking (SST-NFS) INs. In brain slices, we performed paired whole-cell recordings between INs and excitatory projection neurons (PNs) to investigate changes in synaptic physiology. In neonates, we found reduced synaptic input to INs but not PNs, with a concomitant reduction in the frequency of spontaneous network events, which are driven by INs in immature circuits. In mature mice, we found a reduction in the number of PV-FS INs in cortical layers 2/3 and 5. However, changes in PV-FS IN synaptic physiology were cortical layer and PN cell-type dependent. In layer 5, synapses from PV-FS INs to subcortical-projecting PNs were weakened. In contrast, in layer 2/3, synapses to and from PV-FS INs and corticocortical-projecting PNs were strengthened, leading to enhanced feedforward inhibition of input from layer 4. Finally, we found a novel synaptic deficit among SST-NFS INs, in which excitatory synapses from layer 2/3 PNs failed to facilitate. Our data highlight that changes in unitary synaptic dynamics among INs in ASD depend on neuronal cell-type.
PubMed: 38895260
DOI: 10.1101/2024.06.07.597984 -
BioRxiv : the Preprint Server For... Jun 2024is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors....
is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work using transgenic mouse models suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. However, there is conflicting evidence regarding the relative roles of excitatory projection neurons and inhibitory interneurons in generating abnormal cognitive and behavioral phenotypes. Here, we conditionally knocked out either one or both copies of from excitatory projection neuron progenitors and systematically investigated the effects on intrinsic membrane properties, synaptic physiology, social behavior, and seizure susceptibility. We found that disrupting expression in excitatory neurons alters their membrane properties, including hyperpolarizing action potential threshold; however, these changes depend on neuronal subtype. Using paired whole-cell recordings, we found increased synaptic connectivity rate between projection neurons. Furthermore, we found reduced strength of excitatory synapses to parvalbumin (PV)-expression inhibitory interneurons. These data suggest an increase in the ratio of excitation to inhibition. However, the strength of inhibitory synapses from PV interneurons to excitatory neurons was enhanced, which may rebalance this ratio. Indeed, haploinsufficiency in projection neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory projection neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.
PubMed: 38895205
DOI: 10.1101/2024.06.04.597344