1. Boyle N, Li Y, Sun X, Xu P, Lai CH, Betts S, Guo D, Simha R, Zeng C, Du J, Lu H. MeCP2 Deficiency Alters the Response Selectivity of Prefrontal Cortical Neurons to Different Social Stimuli. eNeuro;2024 (Sep);11(9)

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MeCP2 gene, is characterized by cognitive and social deficits. Previous studies have noted hypoactivity in the medial prefrontal cortex (mPFC) pyramidal neurons of MeCP2-deficient mice (RTT mice) in response to both social and nonsocial stimuli. To further understand the neural mechanisms behind the social deficits of RTT mice, we monitored excitatory pyramidal neurons in the prelimbic region of the mPFC during social interactions in mice. These neurons’ activity was closely linked to social preference, especially in wild-type mice. However, RTT mice showed reduced social interest and corresponding hypoactivity in these neurons, indicating that impaired mPFC activity contributes to their social deficits. We identified six mPFC neural ensembles selectively tuned to various stimuli, with RTT mice recruiting fewer neurons to ensembles responsive to social interactions and consistently showing lower stimulus-ON ensemble transient rates. Despite these lower rates, RTT mice exhibited an increase in the percentage of social-ON neurons in later sessions, suggesting a compensatory mechanism for the decreased firing rate. This highlights the limited plasticity in the mPFC caused by MeCP2 deficiency and offers insights into the neural dynamics of social encoding. The presence of multifunctional neurons and those specifically responsive to social or object stimuli in the mPFC emphasizes its crucial role in complex behaviors and cognitive functions, with selective neuron engagement suggesting efficiency in neural activation that optimizes responses to environmental stimuli.

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2. Campos JMB, de Aguiar da Costa M, de Rezende VL, Costa RRN, Ebs MFP, Behenck JP, de Roch Casagrande L, Venturini LM, Silveira PCL, Réus GZ, Gonçalves CL. Animal Model of Autism Induced by Valproic Acid Combined with Maternal Deprivation: Sex-Specific Effects on Inflammation and Oxidative Stress. Mol Neurobiol;2024 (Sep 24)

Autism spectrum disorder (ASD) etiology probably involves a complex interplay of both genetic and environmental risk factors, which includes pre- and perinatal exposure to environmental stressors. Thus, this study evaluated the effects of prenatal exposure to valproic acid (VPA) combined with maternal deprivation (MD) on behavior, oxidative stress parameters, and inflammatory state at a central and systemic level in male and female rats. Pregnant Wistar rats were exposed to VPA during gestation, and the offspring were submitted to MD. Offspring were tested for locomotor and social behavior; rats were euthanized, where the cerebellum, posterior cortex, prefrontal cortex, and peripheric blood were collected for oxidative stress and inflammatory analysis. It was observed that young rats (25-30 days old) exposed only to VPA presented a lower social approach when compared to the control group. VPA + MD rats did not present the same deficit. Female rats exposed to VPA + MD presented oxidative stress in all brain areas analyzed. Male rats in the VPA and VPA + MD groups presented oxidative stress only in the cerebellum. Regarding inflammatory parameters, male rats exposed only to MD exhibited an increase in pro-inflammatory cytokines in the blood and in the cortex total. The same was observed in females exposed only to VPA. Animals exposed to VPA + MD showed no alterations in the cytokines analyzed. In summary, gestational (VPA) and perinatal (MD) insults can affect molecular mechanisms such as oxidative stress and inflammation differently depending on the sex and brain area analyzed. Combined exposition to VPA and MD triggers oxidative stress especially in female brains without evoking an inflammatory response.

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3. Dumontier D, Liebman SA, Le VH, George S, Valdemar D, Van Aelst L, Pouchelon G. Restoring transient connectivity during development improves dysfunctions in fragile X mice. bioRxiv;2024 (Sep 9)

Early-generated circuits are critical for the maturation of cortical network activity and the formation of excitation/inhibition (E/I) balance. This process involves the maturation of specific populations of inhibitory neurons. While parvalbumin (PV)-expressing neurons have been associated with E/I impairments observed in neurodevelopmental disorders, somatostatin-expressing (SST) neurons have recently been shown to regulate PV neuron maturation by controlling neural dynamics in the developing cortex. SST neurons receive transient connections from the sensory thalamus, yet the implications of transient connectivity in neurodevelopmental disorders remain unknown. Here, we show that thalamocortical connectivity to SST neurons is persistent rather than transient in a mouse model of Fragile X syndrome. We were able to restore the transient dynamics using chemogenetics, which led to the recovery of fragile X-associated dysfunctions in circuit maturation and sensory-dependent behavior. Overall, our findings unveil the role of early transient dynamics in controlling downstream maturation of sensory functions.

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4. Frost F, Nagano M, Zane E. Autistic and non-autistic adults use discourse context to determine a speaker’s intention to request. Cogn Process;2024 (Sep 24)

The current study focuses on how autistic adults utilize context to determine whether ambiguous utterances (e.g., « I’m thirsty ») are intended as indirect requests or as literal comment/questions. Two questions are addressed: (1) How do autistic adults compare to neurotypical adults in using context to interpret an utterance’s intention as either literal or a request? (2) What cognitive mechanisms correlate with indirect request interpretation, and are these different for participants in each group? Twenty-six autistic and 26 neurotypical college students participated, engaging in an online experiment where they read narratives that ended with utterances open to literal or request interpretations, based on context. After each narrative, participants selected the best paraphrase of the utterance from two options, literal versus request. Following this task, participants completed two mentalizing measures (a false belief and emotion-identification task) and several executive functioning tests. The best model for predicting paraphrase choice included scores on the emotion-identification task and context as main effects, along with the interaction between both. Participants with higher emotion-identification test scores were more likely to provide correct paraphrases. Models including group as a main effect and/or interaction were not better at fitting the data, nor were any models that included executive functioning measures as main effects or interactions. Emotion-identification test scores, but not autism diagnosis, predict how adults infer whether an utterance is a request. Findings suggest that autistic adults use context similarly to neurotypical adults when interpreting requests, and that similar processes underlie performance for each group.

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5. Katsanevaki D, Till SM, Buller-Peralta I, Nawaz MS, Louros SR, Kapgal V, Tiwari S, Walsh D, Anstey NJ, Petrović NG, Cormack A, Salazar-Sanchez V, Harris A, Farnworth-Rowson W, Sutherland A, Watson TC, Dimitrov S, Jackson AD, Arkell D, Biswal S, Dissanayake KN, Mizen LAM, Perentos N, Jones MW, Cousin MA, Booker SA, Osterweil EK, Chattarji S, Wyllie DJA, Gonzalez-Sulser A, Hardt O, Wood ER, Kind PC. Key roles of C2/GAP domains in SYNGAP1-related pathophysiology. Cell Rep;2024 (Sep 24);43(9):114733.

Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency. However, some affected individuals carry missense mutations in its calcium/lipid binding (C2) and GAP domains, suggesting that many clinical features result from loss of functions carried out by these domains. To test this hypothesis, we targeted the exons encoding the C2 and GAP domains of SYNGAP. Rats heterozygous for this deletion exhibit reduced exploration and fear extinction, altered social investigation, and spontaneous seizures-key phenotypes shared with Syngap heterozygous null rats. Together, these findings indicate that the reduction of SYNGAP C2/GAP domain function is a main feature of SYNGAP haploinsufficiency. This rat model provides an important system for the study of ID, autism, and epilepsy.

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6. Lin J, Xu X, Li C, Kendrick T, He WQ. Multiple developmental disabilities among American children: prevalence and secular trends 2016-2022. Public Health;2024 (Sep 24);237:22-29.

OBJECTIVES: We aimed to estimate the prevalence of multiple developmental disabilities, identify associated characteristics, and examine trends among American children from 2016 to 2022. STUDY DESIGN: This was a cross-sectional study. METHODS: Using the National Survey of Children’s Health data from 2016 to 2022, we estimated the prevalence of multiple developmental disabilities among children aged 3-17 years. Multiple developmental disabilities were defined as two or more concurrent disabilities from 12 common disabilities. Trends were investigated using log-linear regression. Multivariate log-binominal regression was used to compare the prevalence prior to the COVID-19 pandemic (2016-2019) with prevalence during the COVID-19 pandemic (2020-2022). RESULTS: From 239,534 eligible children (mean age = 10.1 years; male = 51.7%), we found the overall prevalence of multiple developmental disabilities was 10.6%. The most predominant phenotype was attention-deficit/hyperactivity disorder concurrent with behavioural problems (2.1%). Higher prevalence was found among boys, non-Hispanic black children, those from low-household-income families and from families with lower education levels. Prevalence of multiple developmental disabilities increased from 9.8% in 2016 to 11.5% in 2022 (P = 0.014) with significantly higher prevalence during COVID-19 pandemic than before (11.2% vs 10.1%). These increases were found consistently across most sociodemographic groups. CONCLUSIONS: Children from certain socio-disadvantaged groups were disproportionally affected by multiple developmental disabilities, highlighting the need for targeted strategies to improve health. The increasing prevalence during the pandemic suggests the need for ongoing monitoring of the trend and the impact of these conditions.

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7. Ltaief SM, Nour-Eldine W, Manaph NPA, Tan TM, Anuar ND, Bensmail I, George J, Abdesselem HB, Al-Shammari AR. Dysregulated plasma autoantibodies are associated with B cell dysfunction in young Arab children with autism spectrum disorder in Qatar. Autism Res;2024 (Sep 24)

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, as well as the occurrence of stereotyped and repetitive behaviors. Previous studies have provided solid evidence of dysregulated immune system in ASD; however, limited studies have investigated autoantibody profiles in individuals with ASD. This study aims to screen plasma autoantibodies in a well-defined cohort of young children with ASD (n = 100) and their matched controls (n = 60) utilizing a high-throughput KoRectly Expressed (KREX) i-Ome protein-array technology. We identified differential protein expression of 16 autoantibodies in ASD, which were correlated with differential gene expression of these markers in independent ASD cohorts. Meanwhile, we identified a distinct list of 33 autoantibodies associated with ASD severity; several of which were correlated with maternal age and birth weight in ASD. In addition, we found dysregulated numbers of circulating B cells and activated HLADR+ B cells in ASD, which were correlated with altered levels of several autoantibodies. Further in-depth analysis of B cell subpopulations revealed an increased frequency of activated naïve B cells in ASD, as well as an association of resting naïve B cells and transitional B cells with ASD severity. Pathway enrichment analysis revealed disrupted MAPK signaling in ASD, suggesting a potential relevance of this pathway to altered autoantibodies and B cell dysfunction in ASD. Finally, we found that a combination of eight autoantibodies associated with ASD severity showed an area under the curve (ROC-AUC) of 0.937 (95% CI = 0.890, 0.983; p < 0.001), which demonstrated the diagnostic accuracy of the eight-marker signature in the severity classification of ASD cases. Overall, this study determined dysregulated autoantibody profiles and B cell dysfunction in children with ASD and identified an eight-autoantibody panel for ASD severity classification.

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8. Martinez B, Peplow PV. Autism spectrum disorder: difficulties in diagnosis and microRNA biomarkers. Neural Regen Res;2024 (Sep 24)

We performed a PubMed search for microRNAs in autism spectrum disorder that could serve as diagnostic biomarkers in patients and selected 17 articles published from January 2008 to December 2023, of which 4 studies were performed with whole blood, 4 with blood plasma, 5 with blood serum, 1 with serum neural cell adhesion molecule L1-captured extracellular vesicles, 1 with blood cells, and 2 with peripheral blood mononuclear cells. Most of the studies involved children and the study cohorts were largely males. Many of the studies had performed microRNA sequencing or quantitative polymerase chain reaction assays to measure microRNA expression. Only five studies had used real-time polymerase chain reaction assay to validate microRNA expression in autism spectrum disorder subjects compared to controls. The microRNAs that were validated in these studies may be considered as potential candidate biomarkers for autism spectrum disorder and include miR-500a-5p, -197-5p, -424-5p, -664a-3p, -365a-3p, -619-5p, -664a- 3p, -3135a, -328-3p, and -500a-5p in blood plasma and miR-151a-3p, -181b-5p, -320a, -328, -433, -489, -572, -663a, -101-3p, -106b-5p, -19b-3p, -195-5p, and -130a-3p in blood serum of children, and miR-15b-5p and -6126 in whole blood of adults. Several important limitations were identified in the studies reviewed, and need to be taken into account in future studies. Further studies are warranted with children and adults having different levels of autism spectrum disorder severity and consideration should be given to using animal models of autism spectrum disorder to investigate the effects of suppressing or overexpressing specific microRNAs as a novel therapy.

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9. Neelotpol S, Rezwan R, Singh T, Mayesha, II, Saba S, Jamiruddin MR. Pharmacological intervention of behavioural traits and brain histopathology of prenatal valproic acid-induced mouse model of autism. PLoS One;2024;19(9):e0308632.

Autism spectrum disorder (ASD) is one of the leading causes of distorted social communication, impaired speech, hyperactivity, anxiety, and stereotyped repetitive behaviour. The aetiology of ASD is complex; therefore, multiple drugs have been suggested to manage the symptoms. Studies with histamine H3 receptor (H3R) blockers and acetylcholinesterase (AchE) blockers are considered potential therapeutic agents for the management of various cognitive impairments. Therefore, the aim of this study was to evaluate the neuro-behavioural effects of Betahistine, an H3R antagonist, and Donepezil, an acetylcholinesterase inhibitor on Swiss albino mouse model of autism. The mice were intraperitoneally injected with valproic acid (VPA) on the embryonic 12.5th day to induce autism-like symptoms in their offspring. This induced autism-like symptoms persists throughout the life. After administration of different experimental doses, various locomotor tests: Open Field, Hole-Board, Hole Cross and behavioural tests by Y-Maze Spontaneous Alternation and histopathology of brain were performed and compared with the control and negative control (NC1) groups of mice. The behavioural Y-Maze test exhibits significant improvement (p <0.01) on the short term memory of the test subjects upon administration of lower dose of Betahistine along with MAO-B inhibitor Rasagiline once compared with the NC1 group (VPA-exposed mice). Furthermore, the tests showed significant reduction in locomotion in line crossing (p <0.05), rearing (p <0.001) of the Open Field Test, and the Hole Cross Test (p <0.01) with administration of higher dose of Betahistine. Both of these effects were observed upon administration of acetylcholinesterase inhibitor, Donepezil. Brain-histopathology showed lower neuronal loss and degeneration in the treated groups of mice in comparison with the NC1 VPA-exposed mice. Administration of Betahistine and Rasagiline ameliorates symptoms like memory deficit and hyperactivity, proving their therapeutic effects. The effects found are dose dependent. The findings suggest that H3R might be a viable target for the treatment of ASD.

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10. Prakasam R, Determan J, Narasimhan M, Shen R, Saleh M, Chapman G, Kaushik K, Gontarz P, Meganathan K, Hakim B, Zhang B, Huettner JE, Kroll KL. Autism and Intellectual Disability-Associated MYT1L Mutation Alters Human Cortical Interneuron Differentiation, Maturation, and Physiology. bioRxiv;2024 (Sep 12)

MYT1L is a neuronal transcription factor highly expressed in the developing and adult brain. While pathogenic MYT1L mutation causes neurodevelopmental disorders, these have not been characterized in human models of neurodevelopment. Here, we defined the consequences of pathogenic MYT1L mutation in human pluripotent stem cell-derived cortical interneurons. During differentiation, mutation reduced MYT1L expression and increased progenitor cell cycle exit and neuronal differentiation and synapse-related gene expression, morphological complexity, and synaptic puncta formation. Conversely, interneuron maturation was compromised, while variant neurons exhibited altered sodium and potassium channel activity and reduced function in electrophysiological analyses. CRISPRi-based knockdown similarly impaired interneuron differentiation and maturation, supporting loss of function-based effects. We further defined MYT1L genome-wide occupancy in interneurons and related this to the transcriptomic dysregulation resulting from MYT1L mutation, to identify direct targets that could mediate these phenotypic consequences. Together, this work delineates contributors to the etiology of neurodevelopmental disorders resulting from MYT1L mutation.

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11. Rapaport H, Sowman PF. Examining predictive coding accounts of typical and autistic neurocognitive development. Neurosci Biobehav Rev;2024 (Sep 24):105905.

Predictive coding has emerged as a prominent theoretical framework for understanding perception and its neural underpinnings. There has been a recent surge of interest in the predictive coding framework across the mind sciences. However, comparatively little of the research in this field has investigated the neural underpinnings of predictive coding in young neurotypical and autistic children. This paper provides an overview of predictive coding accounts of typical and autistic neurocognitive development and includes a review of the current electrophysiological evidence supporting these accounts. Based on the current evidence, it is clear that more research in pediatrics is needed to evaluate predictive coding accounts of neurocognitive development fully. If supported, these accounts could have wide-ranging practical implications for pedagogy, parenting, artificial intelligence, and clinical approaches to helping autistic children manage the barrage of everyday sensory information.

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12. Raza MH, Bhutta ME, Siddique MH. Shifting Focus: The Need for Early Intervention and Safer Alternatives in Autism Spectrum Disorder Treatment. Trends Psychiatry Psychother;2024 (Sep 24)

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13. Schwartz AJ, Ambardekar AP. Service Animals. Jama;2024 (Sep 24);332(12):1022-1023.

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14. Shen C, Zhu X, Chang H, Li C, Hou M, Chen L, Lu C, Zhou Z, Ji M, Xu Z. The rebalancing of the immune system at the maternal-fetal interface ameliorates autism-like behavior in adult offspring. Cell Rep;2024 (Sep 24);43(10):114787.

Maternal immune activation (MIA) is critical for imparting neuropathology and altered behaviors in offspring; however, maternal-fetal immune cell populations have not been thoroughly investigated in MIA-induced autism spectrum disorders (ASDs). Here, we report the single-cell transcriptional landscape of placental cells in both PBS- and poly(I:C)-induced MIA dams. We observed a decrease in regulatory T (Treg) cells but an increase in the M1 macrophage population at the maternal-fetal interface in MIA dams. Based on the Treg-targeting approach, we investigate an immunoregulatory protein, the helminth-derived heat shock protein 90α (Sjp90α), that induces maternal Treg cells and subsequently rescues the autism-like behaviors in adult offspring. Furthermore, in vivo depletion of maternal macrophages attenuates placental inflammatory reaction and reverses behavioral abnormalities in adult offspring. Notably, Sjp90α induces CD4(+) T cell differentiation via scavenger receptor A (SR-A) on the macrophage in vitro. Our findings suggest a maternal Treg-targeted approach to alleviate MIA-induced autism-like behavior in adult offspring.

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15. Zhang X, Wang K, Jia H, He Q, Zhang X, Wang E. Individuals with high autism traits show top-down attention bias towards threatening stimuli. Biol Psychol;2024 (Sep 21);193:108875.

Individuals with autistic traits (AT) are widely distributed in the general population. Strengthening understanding of AT can provide a broader perspective for autism research as well as more accurate diagnosis and personalized treatment plans for clinical practice. Previous studies on attention bias among high-AT individuals have yielded inconsistent results, which may relate to different stages of attention. In this study, we selected two groups with high and low level AT from the general population, and then adopted the odd-one-out search task, combined with Event-related potential (ERP) technique, conducted both attention orientation and attention dissociation tasks, to explore attention bias and electroencephalogram (EEG) characteristics towards threatening emotional faces in these groups. The behavioral data showed no accelerated attention orientation to angry faces and neutral faces; however, there was attention dissociation difficulty for angry faces. Compared with low-AT individuals, the EEG results showed that high-AT individuals have acceleration of attention orientation and attention dissociation difficulty for threatening emotional faces. From the perspective of top-down concept-driven processing, these findings suggest that high-AT individuals have attention bias for cognitive processing of threatening stimuli, which is mainly due to acceleration of attention orientation and attention dissociation difficulties for threatening information.

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