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Scientific Reports Jun 2024Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of...
Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of various neurological disorders. Most positive allosteric modulators (PAMs) of mAChR enhance agonist affinity and potency, while very few PAMs (e.g., amiodarone) selectively enhance G protein coupling efficacy. The key structural features of amiodarone responsible for enhancement of mAChR efficacy were examined in CHO cells expressing M receptors. Subsequent incorporation of these structural features into previously identified allosteric modulators of potency (i.e., n-benzyl isatins) generated ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable ligands include 8a, c which respectively demonstrated the strongest binding affinity and the most robust enhancement of mAChR efficacy as calculated from an allosteric operational model. Amiodarone derivatives and hybrid ligands were additionally screened in wildtype zebrafish (Danio rerio) to provide preliminary in vivo toxicity data as well as to observe effects on locomotor and turning behaviors relative to other mAChR PAMs. Several compounds, including 8a, c, reduced locomotor activity and increased measures of turning behaviors in zebrafish, suggesting that allosteric modulation of muscarinic receptor efficacy might be useful in the treatment of repetitive behaviors associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders.
Topics: Animals; Zebrafish; Receptor, Muscarinic M1; Allosteric Regulation; CHO Cells; Cricetulus; Acetylcholine; Locomotion; Ligands; Muscarinic Agonists
PubMed: 38942828
DOI: 10.1038/s41598-024-65445-y -
Biochemical Pharmacology Jun 2024GPR56, also known as GPR56/ADGRG1, is a member of the ADGRG subgroup belonging to adhesion G protein-coupled receptors (aGPCRs). aGPCRs are the second largest subfamily... (Review)
Review
GPR56, also known as GPR56/ADGRG1, is a member of the ADGRG subgroup belonging to adhesion G protein-coupled receptors (aGPCRs). aGPCRs are the second largest subfamily of the GPCR superfamily, which is the largest family of membrane protein receptors in the human genome. Studies in recent years have demonstrated that GPR56 is integral to the normal development of the brain and functions as an important player in cortical development, suggesting that GPR56 is involved in many physiological processes. Indeed, aberrant expression of GPR56 has been implicated in multiple neurological and psychiatric disorders, including bilateral frontoparietal polymicrogyria (BFPP), depression and epilepsy. In a recent study, it was found that upregulated expression of GPR56 reduced depressive-like behaviours in an animal model of depression, indicating that GPR56 plays an important role in the antidepressant response. Given the link of GPR56 with the antidepressant response, the function of GPR56 has become a focus of research. Although GPR56 may be a potential target for the development of antidepressants, the underlying molecular mechanisms remain largely unknown. Therefore in this review, we will summarize the latest findings of GPR56 function in neurological and psychiatric disorders (depression, epilepsy, autism, and BFPP) and emphasize the mechanisms of GPR56 in activation and signalling in those conditions. After reviewing several studies, attributing to its significant biological functions and exceptionally long extracellular N-terminus that interacts with multiple ligands, we draw a conclusion that GPR56 may serve as an important drug target for neuropsychological diseases.
PubMed: 38942087
DOI: 10.1016/j.bcp.2024.116395 -
Cell Genomics Jun 2024Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest...
Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest multi-brain-region bulk transcriptional datasets for the rhesus macaque and characterized sex-biased gene expression patterns to investigate the translatability of this species for sex-biased neurological conditions. We identify patterns similar to those in humans, which are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and support the rhesus macaque model for the translational study of these conditions.
PubMed: 38942023
DOI: 10.1016/j.xgen.2024.100589 -
Infant Behavior & Development Jun 2024Autism Spectrum Disorder is a highly heritable condition characterized by sociocommunicative difficulties, frequently entailing language atypicalities that extend to...
Autism Spectrum Disorder is a highly heritable condition characterized by sociocommunicative difficulties, frequently entailing language atypicalities that extend to infants with a familial history of autism. The developmental mechanisms underlying these difficulties remain unknown. Detecting temporal synchrony between the lip movements and the auditory speech of a talking face and selectively attending to the mouth support typical early language acquisition. This preliminary eye-tracking study investigated whether these two fundamental mechanisms atypically function in infant siblings. We longitudinally tracked the trajectories of infants at elevated and low-likelihood for autism in these two abilities at 4, 8, and 12 months (n = 29). We presented two talking faces (synchronous and asynchronous) while recording infants' gaze to the talker's eyes and mouth. We found that infants detected temporal asynchronies in talking faces at 12 months regardless of group. However, compared to their typically developing peers, infants with an elevated likelihood of autism showed reduced attention to the mouth at the end of the first year and no variations in their interest to this area across time. Our findings provide preliminary evidence on a potentially atypical trajectory of reduced mouth-looking in audiovisual speech during the first year in infant siblings, with potential cascading consequences for language development, thus contributing to domain-general accounts of emerging autism.
PubMed: 38941721
DOI: 10.1016/j.infbeh.2024.101973 -
Research in Developmental Disabilities Jun 2024Virtual Reality (VR) based diagnostic and therapeutic interventions have opened up new possibilities for addressing the challenges in identifying and treating... (Review)
Review
Effect of immersive virtual reality-based training on cognitive, social, and emotional skills in children and adolescents with autism spectrum disorder: A meta-analysis of randomized controlled trials.
BACKGROUND
Virtual Reality (VR) based diagnostic and therapeutic interventions have opened up new possibilities for addressing the challenges in identifying and treating individuals with Autism Spectrum Disorders (ASD).
AIM
To conduct a systematic review and meta-analysis of Randomized Controlled Trials to investigate the impact of Immersive VR techniques on the cognitive, social, and emotional skills of under-18 children and adolescents with ASD.
METHODS AND PROCEDURES
Four databases were systematically searched as per "Preferred Reporting Items for Systematic Reviews and Meta-analyses" guidelines and assessed six RCTs for further analysis. The Cochrane Risk of Bias tool was used to assess the methodological quality of the studies.
OUTCOMES
Pooled results favoured VR and reported significant differences between experimental and control groups concerning social skills (SMD:1.43; 95 % CI: 0.01-2.84; P: 0.05), emotional skills (SMD: 2.45; 95 % CI: 0.21-4.18; P: 0.03) and cognitive skills.
CONCLUSION
VR offers an array of benefits that make it a promising tool for children and adolescents with ASD to improve their cognitive, social and emotional skills in a safe and supportive setting. However, accessibility, affordability, customization, and cost are also significant aspects to consider when developing and implementing VR-based interventions for ASD.
PubMed: 38941690
DOI: 10.1016/j.ridd.2024.104771 -
The British Journal of General Practice Jun 2024
PubMed: 38816239
DOI: 10.3399/bjgp24X738441 -
Journal of Autism and Developmental... Jun 2024Racial differences in prevalence rates of autism spectrum disorder (ASD) have shifted in the United States (US) since the 1990s. This review addresses the nature and...
PURPOSE
Racial differences in prevalence rates of autism spectrum disorder (ASD) have shifted in the United States (US) since the 1990s. This review addresses the nature and context of this shift and discusses potential contributing factors and areas for future research.
METHODS
Seventeen population-based epidemiological birth cohort studies on ASD prevalence in the US that included race as a variable are included in the review. Studies were identified via a keyword search on PubMed. To be included, studies were required to include race or ethnicity as a variable in the prevalence estimates, include at least 1000 cases with autism, and be published in English by June 3rd, 2023.
RESULTS
Results suggest that in nearly all birth cohorts prior to 2010, ASD prevalence rates were highest among White children. ASD prevalence rates among Black, Hispanic, and Asian/Pacific Islander (API) children (22.3, 22.5, and 22.2 per 1000, respectively) surpassed prevalence rates among White children (21.2 per 1000) in the 2010 birth cohort and continued to increase in the 2012 birth cohorts.
CONCLUSIONS
There are persistent racial differences in ASD prevalence in the US, and these differences were inverted after 2010, when ASD prevalence among Black, Hispanic, & API children surpassed ASD prevalence among White children. Possible drivers of this racial repatterning of ASD prevalence include changes in ASD screening and diagnosis, changes to health insurance policy, changes to immigration policy, and increased education attainment by minority groups.
PubMed: 38941049
DOI: 10.1007/s10803-024-06403-5 -
Journal of Autism and Developmental... Jun 2024Many individuals with autism spectrum disorder (ASD) experience challenges with facial emotion recognition (FER), which may exacerbate social difficulties in ASD. Few...
PURPOSE
Many individuals with autism spectrum disorder (ASD) experience challenges with facial emotion recognition (FER), which may exacerbate social difficulties in ASD. Few studies have examined whether FER can be experimentally manipulated and improved for autistic people. This study utilized a randomized controlled trial design to examine acceptability and preliminary clinical impact of a novel mixed reality-based neurofeedback program, FER Assistant, using EEG brain computer interface (BCI)-assisted technology to improve FER for autistic adolescents and adults.
METHODS
Twenty-seven autistic male participants (M age: 21.12 years; M IQ: 105.78; 85% white) were randomized to the active condition to receive FER Assistant (n = 17) or waitlist control (n = 10). FER Assistant participants received ten sessions utilizing BCI-assisted neurofeedback training in FER. All participants, regardless of randomization, completed a computerized FER task at baseline and endpoint.
RESULTS
Results partially indicated that FER Assistant was acceptable to participants. Regression analyses demonstrated that participation in FER Assistant led to group differences in FER at endpoint, compared to a waitlist control. However, analyses examining reliable change in FER indicated no reliable improvement or decline for FER Assistant participants, whereas two waitlist participants demonstrated reliable decline.
CONCLUSION
Given the preliminary nature of this work, results collectively suggest that FER Assistant may be an acceptable intervention. Results also suggest that FER may be a potential mechanism that is amenable to intervention for autistic individuals, although additional trials using larger sample sizes are warranted.
PubMed: 38941048
DOI: 10.1007/s10803-024-06436-w -
Journal of Autism and Developmental... Jun 2024Previous research has found that rural children are more likely to be disabled but are less likely to receive care. Both rural and disabled children were significantly...
Previous research has found that rural children are more likely to be disabled but are less likely to receive care. Both rural and disabled children were significantly impacted by the pandemic, particularly in terms of service utilization. Therefore, this study seeks to identify rural-urban differences in the prevalence of various disability indicators and in the receipt of educational and healthcare services. Data from 12,828 children aged 2-17 who participated in the 2021-2022 National Health Interview Survey (NHIS) was used to examine rural-urban differences in three different disability indicators and in education and health services utilization. Disability indicators included the Washington Group Short Set Composite Disability Indicator, a developmental disability indicator, and a neurodivergence indicator. Bivariate analysis, via Rao-Scott chi-square tests, was used to examine rural-urban disparities. Compared to their urban counterparts, rural children were more likely to have a positive Washington Group Short Set Composite Disability Indicator (14.3% vs. 10.6%) and neurodivergence indicator (17Ð.3% vs. 14.1%). Rural children with disabilities were more likely to have received prescription medication for behavioral, mental, or emotional health or concentration in the past year than urban children (34.2% vs. 25.9%). There was no rural-urban difference in the prevalence of developmental disabilities or other forms of health care use and special education participation. This report highlights the need for further investigation into underlying causes of rural-urban disparities in the prevalence of disabilities, as well as the need for continued support for programs and policies designed to support rural children with disabilities.
PubMed: 38941047
DOI: 10.1007/s10803-024-06434-y -
Autism Research : Official Journal of... Jun 2024Developmental antecedents of autism may affect parent-infant interactions (PII), altering the context in which core social skills develop. While studies have identified...
Developmental antecedents of autism may affect parent-infant interactions (PII), altering the context in which core social skills develop. While studies have identified differences in PII between infants with and without elevated likelihood (EL) for autism, samples have been small. Here, we examined whether previously reported differences are replicable. From a longitudinal study of 113 EL and 27 typical likelihood infants (TL), 6-min videotaped unstructured PII was blind rated at 8 and 14 months on eight interactional qualities. Autism outcome was assessed at 36 months. Linear mixed-effects models found higher parent sensitive responsiveness, nondirectiveness, and mutuality ratings in TL than EL infants with and without later autism. PII qualities at 8 (infant positive affect, parent directiveness) and 14 months (infant attentiveness to parent, mutuality) predicted 3-year autism. Attentiveness to parent decreased between 8 and 14 months in EL infants with later autism. This larger study supports previous findings of emerging alterations in PII in this group and extends on this by detecting earlier (8-month) predictive effects of PII for autism outcome and a more marked trajectory of decreased social attentiveness. The findings strengthen the evidence base to support the implementation of early preemptive interventions to support PII in infants with early autism signs.
PubMed: 38940216
DOI: 10.1002/aur.3190