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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 -
Frontiers in Psychiatry 2024Caregivers of children with autism spectrum disorder (ASD) in China often experience alienation due to societal stigma. While this alienation detrimentally impacts their...
INTRODUCTION
Caregivers of children with autism spectrum disorder (ASD) in China often experience alienation due to societal stigma. While this alienation detrimentally impacts their mental well-being, family resilience serves as a protective factor. Previous research has predominantly examined the social support derived from social activities but has neglected to delve into the specific patterns of these activities. The primary objective of this study was twofold: firstly, to gain insights into the various social activities engaged in by caregivers of children with autism in China, and secondly, to ascertain the influence of these social activities on alienation and family resilience.
METHODS
Between June and August 2023, a cross-sectional survey was carried out across multiple cities in Jilin Province, aiming to gather data from a total of 205 Chinese caregivers of children with autism. Data collection was conducted through the utilization of a structured questionnaire. The assessment of social activity involved the completion of 12 questionnaires, while alienation was evaluated using the Generalized Alienation Scale (GSAS), and family resilience was gauged through the Chinese version of the Family Resilience Scale (FaRE). The classification of social activities was conducted through latent class analysis (LCA), while the impact of these social activities on alienation and family resilience was examined using linear regression analysis.
RESULTS
The findings revealed that social activities can be categorized into five types (Low, Self-Recreation, Communication, Web Surfing, High). Communication social activities were found to reduce family resilience(β=.332, p<0.01), while high social activities were associated with reduced alienation(β=-.349, p<0.05) and increased family resilience(β=.417, p<0.01).
CONCLUSION
Supporting these particular types of social activities has the potential to reduce alienation and bolster family resilience among caregivers for children with autism in China.
PubMed: 38895029
DOI: 10.3389/fpsyt.2024.1406073 -
Journal of Clinical Medicine May 2024: The intranasal delivery of various neurotropic substances is considered a new attractive therapeutic approach for treating neuropathologies associated with...
: The intranasal delivery of various neurotropic substances is considered a new attractive therapeutic approach for treating neuropathologies associated with neuroinflammation and altered regeneration. Specific language impairment (SLI) that arises as a result of damage to the cortical speech zones during the developmental period is one of the most common problems in preschool children, and it is characterized by persistent difficulties in the acquisition, understanding, and use of language. This study's objective is to evaluate the efficacy and safety of intranasal immunotherapy using the M2 macrophage secretome as a rich source of immunoregulatory and neurotrophic factors for the treatment of severe language impairment in children. : Seventy-one children (54 boys and 17 girls, aged 3 to 13 years) were recruited to participate in a clinical trial (NCT04689282) in two medical centers. The children were examined before, 1 month after, and 6 months after the start of therapy. In the vast majority of children (55/71), language impairment was associated with autistic-like symptoms and attention deficit hyperactivity disorder (ADHD). : Daily intranasal inhalations of M2 macrophage-conditioned medium (for 30 days) were well tolerated and led to a decrease in the severity of language impairments, autistic-like behavior, and ADHD symptoms. The clinical effect appeared within a month after the first procedure and persisted or intensified during a 6-month follow-up. Two-thirds of the children showed a clear clinical improvement, while the rest had less pronounced improvement. : Thus, the use of the M2 macrophage secretome and its intranasal delivery is safe, well tolerated, and clinically effective in children with severe language impairments.
PubMed: 38892790
DOI: 10.3390/jcm13113079 -
Nutrients May 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder identified by impairments in common social interactions and repetitive behaviors. In ASD patients,...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder identified by impairments in common social interactions and repetitive behaviors. In ASD patients, substantial morphological alterations have been observed in the hippocampus, which represents an important region for the development of social skills. Melatonin, commonly found in many foods and plants, is also produced by the pineal gland. This indolamine, known to regulate the circadian rhythm, shows antioxidant and anti-inflammatory properties. We therefore hypothesized that melatonin may reduce oxidative stress and inflammation in the hippocampus of ASD patients. We explored our hypothesis using the BTBR mouse, a well-regarded murine transgenic model for ASD. Immediately after weaning, male BTBR and C57BL/6 mice underwent an 8-week treatment with melatonin or vehicle. Later, through immunohistochemistry and the immunoblotting analysis of the hippocampus, we evaluated the overall expression and cellular localization of Nrf2 and SOD1, two enzymes involved in the oxidative stress response. Similarly, we evaluated NLRP3 and NFkB, two mediators of inflammation, and GAD67, an enzyme responsible for the synthesis of GABA. Ultimately, we addressed melatonin's potential to regulate iron metabolism through a DAB-enhanced Perls reaction assay. Results showed melatonin's potential for modulating the analyzed markers in BTBR mice, suggesting a potential neuroprotective effect in ASD patients.
Topics: Animals; Melatonin; Hippocampus; Male; Neuroprotective Agents; Mice; Mice, Inbred C57BL; Oxidative Stress; Disease Models, Animal; Autism Spectrum Disorder; Antioxidants; Mice, Transgenic; NF-E2-Related Factor 2; Inflammation
PubMed: 38892585
DOI: 10.3390/nu16111652 -
International Journal of Molecular... May 2024Autism spectrum disorder (ASD) is a common and highly heritable neurodevelopmental disorder. During the last 15 years, advances in genomic technologies and the... (Review)
Review
Autism spectrum disorder (ASD) is a common and highly heritable neurodevelopmental disorder. During the last 15 years, advances in genomic technologies and the availability of increasingly large patient cohorts have greatly expanded our knowledge of the genetic architecture of ASD and its neurobiological mechanisms. Over two hundred risk regions and genes carrying rare de novo and transmitted high-impact variants have been identified. Additionally, common variants with small individual effect size are also important, and a number of loci are now being uncovered. At the same time, these new insights have highlighted ongoing challenges. In this perspective article, we summarize developments in ASD genetic research and address the enormous impact of large-scale genomic initiatives on ASD gene discovery.
Topics: Humans; Genetic Predisposition to Disease; Risk Factors; Genomics; Autism Spectrum Disorder; Genome-Wide Association Study; Autistic Disorder
PubMed: 38892002
DOI: 10.3390/ijms25115816 -
Biological Research Jun 2024The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and...
Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice.
BACKGROUND
The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown.
RESULTS
Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety.
CONCLUSIONS
These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.
Topics: Animals; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Neurons; Mice; Autistic Disorder; Disease Models, Animal; Male; Cerebral Cortex; Mice, Knockout; Synaptic Transmission; Mice, Inbred C57BL; Female
PubMed: 38890753
DOI: 10.1186/s40659-024-00522-0 -
BMC Psychiatry Jun 2024Difficulties with inhibitory control have been identified in eating disorders (EDs) and neurodevelopmental disorders (NDs; including attention deficit hyperactivity... (Review)
Review
BACKGROUND
Difficulties with inhibitory control have been identified in eating disorders (EDs) and neurodevelopmental disorders (NDs; including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder), and there appear to be parallels between the expression of these impairments. It is theorised that impairments in inhibitory control within NDs may represent a unique vulnerability for eating disorders (EDs), and this same mechanism may contribute to poorer treatment outcomes. This review seeks to determine the state of the literature concerning the role of inhibitory control in the overlap of EDs and neurodivergence.
METHOD
A scoping review was conducted to summarise extant research, and to identify gaps in the existing knowledge base. Scopus, Medline, PsycInfo, Embase, and ProQuest were systematically searched. Studies were included if the study measured traits of ADHD or autism, and symptoms of ED, and required participants to complete a performance task measure of inhibitory control. Where studies included a cohort with both an ND and ED, these results had to be reported separately from cohorts with a singular diagnosis. Studies were required to be published in English, within the last 10 years.
RESULTS
No studies explored the relationship between autism and EDs using behavioural measures of inhibitory control. Four studies exploring the relationship between ADHD and EDs using behavioural measures of inhibitory control met selection criteria. These studies showed a multifaceted relationship between these conditions, with differences emerging between domains of inhibitory control. ADHD symptoms predicted poorer performance on measures of response inhibition in a non-clinical sample; this was not replicated in clinical samples, nor was there a significant association with EDs. Both ADHD and ED symptoms are associated with poor performance on attentional control measures; where these diagnoses were combined, performance was worse than for those with a singular diagnosis of ADHD. This was not replicated when compared to those with only ED diagnoses.
CONCLUSION
Impairments in attentional control may represent a unique vulnerability for the development of an ED and contribute to poor treatment outcomes. Further research is needed to explore the role of inhibitory control in EDs, ADHD and autism, including the use of both self-report and behavioural measures to capture the domains of inhibitory control.
Topics: Humans; Inhibition, Psychological; Feeding and Eating Disorders; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Neurodevelopmental Disorders
PubMed: 38890597
DOI: 10.1186/s12888-024-05837-6 -
Scientific Reports Jun 2024Microtransactions provide optional, virtual, video game goods that, for an additional cost to the player, provide additional game content and alter the gameplay...
Microtransactions provide optional, virtual, video game goods that, for an additional cost to the player, provide additional game content and alter the gameplay experience. Loot boxes-a specific form of microtransaction-offer randomised rewards in exchange for payment, and are argued to be structurally and psychologically similar to gambling. Nascent research suggests that a link exists between autism and both problematic gaming and problematic gambling. Here, we investigated the relationships between autistic characteristics and experiences, and excessive video gaming and microtransaction expenditure. A sample of 1178 adults from Australia, Aotearoa, and The United States were recruited from Prolific Academic, and completed a survey measuring in-game expenditure, autistic characteristics and experiences, problematic gaming, problematic gambling, and risky loot box use. Analyses showed positive associations between autistic characteristics and experiences with problematic gaming and problem gambling symptomatology. However, results also showed a small, negative association between autistic characteristics and experiences and spending on loot boxes when problem gambling symptoms, problematic gaming, and risky loot box use were statistically controlled for. These results suggest that autistic gamers may be vulnerable to problematic gaming and gambling, but that this effect does not extend to the purchasing of microtransactions.
Topics: Humans; Male; Female; Adult; Video Games; Autistic Disorder; Gambling; Middle Aged; Australia; Young Adult; United States; Adolescent; Surveys and Questionnaires; Reward
PubMed: 38890438
DOI: 10.1038/s41598-024-64812-z -
Scientific Reports Jun 2024Face-processing timing differences may underlie visual social attention differences between autistic and non-autistic people, and males and females. This study...
Face-processing timing differences may underlie visual social attention differences between autistic and non-autistic people, and males and females. This study investigates the timing of the effects of neurotype and sex on face-processing, and their dependence on age. We analysed EEG data during upright and inverted photographs of faces from 492 participants from the Longitudinal European Autism Project (141 neurotypical males, 76 neurotypical females, 202 autistic males, 73 autistic females; age 6-30 years). We detected timings of sex/diagnosis effects on event-related potential amplitudes at the posterior-temporal channel P8 with Bootstrapped Cluster-based Permutation Analysis and conducted Growth Curve Analysis (GCA) to investigate the timecourse and dependence on age of neural signals. The periods of influence of neurotype and sex overlapped but differed in onset (respectively, 260 and 310 ms post-stimulus), with sex effects lasting longer. GCA revealed a smaller and later amplitude peak in autistic female children compared to non-autistic female children; this difference decreased in adolescence and was not significant in adulthood. No age-dependent neurotype difference was significant in males. These findings indicate that sex and neurotype influence longer latency face processing and implicates cognitive rather than perceptual processing. Sex may have more overarching effects than neurotype on configural face processing.
Topics: Humans; Female; Male; Adolescent; Child; Adult; Autistic Disorder; Young Adult; Electroencephalography; Brain; Evoked Potentials; Facial Recognition; Sex Characteristics
PubMed: 38890406
DOI: 10.1038/s41598-024-64387-9