Form Of Autism Spectrum Disorder Research Articles

Dysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids.

MEF2C is a critical transcription factor in neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Despite prior animal studies of MEF2C heterozygosity to mimic MHS, MHS-specific mutations have not been investigated previously, particularly in a human context as hiPSCs afford. Here, for the first time, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found that decreased neurogenesis was accompanied by activation of a micro-(mi)RNA-mediated gliogenesis pathway. We also demonstrate network-level hyperexcitability in MHS neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the predominantly extrasynaptic (e)NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks, suggesting that treatment of MHS deficits may possibly help other forms of ASD as well.

Impaired Experience-Dependent Theta Oscillation Synchronization and Inter-Areal Synaptic Connectivity in the Visual Cortex of Fmr1 KO Mice.

Fragile X syndrome (FX) is the most prevalent inheritable form of autism spectrum disorder (ASD), characterized by hypersensitivity, difficulty in habituating to new sensory stimuli, and intellectual disability. Individuals with FX often experience visual perception and learning deficits. Visual experience leads to the emergence of the familiarity-evoked theta band oscillations in the primary visual cortex (V1) and the lateromedial area (LM) of mice. These theta oscillations in V1 and LM are synchronized with each other, providing a mechanism of sensory multi-areal binding. However, how this multi-areal binding and the corresponding theta oscillations are altered in FX is not known. Using iDISCO whole brain clearing with light-sheet microscopy, we quantified immediate early gene Fos expression in V1 and LM, identifying deficits in experience-dependent neural activity in FX mice. We performed simultaneous in vivo recordings with silicon probes in V1 and LM of awake mice and channelrhodopsin-2-assisted circuit mapping (CRACM) in acute brain slices to examine the neural activity and strength of long-range synaptic connections between V1 and LM in both wildtype (WT) and Fmr1 knockout (KO) mice, the model of FX, before and after visual experience. Our findings reveal synchronized familiarity-evoked theta oscillations in V1 and LM, the increased strength of V1→LM functional and synaptic connections, which correlated with the corresponding changes of presynaptic short-term plasticity in WT mice. The LM oscillations were attenuated in FX mice and correlated with impaired functional and synaptic connectivity and short-term plasticity in the feedforward (FF) V1→LM and feedback (FB) LM→V1 pathways. Finally, using 4Pi single-molecule localization microscopy (SMLM) in thick brain tissue, we identified experience-dependent changes in the density and shape of dendritic spines in layer 5 pyramidal cells of WT mice, which correlated with the functional synaptic measurements. Interestingly, there was an increased dendritic spine density and length in naïve FX mice that failed to respond to experience. Our study provides the first comprehensive characterization of the role of visual experience in triggering inter-areal neural synchrony and shaping synaptic connectivity in WT and FX mice.

Level 1 autism spectrum disorder as a risk factor for suicide in a child: case report

Introduction: Suicidal behavior is one in which the individual has thoughts, plans, and actions with the intention of ending their own life. This is a global public health problem. Recently, autism spectrum disorders have begun to be considered risk factor for suicidal behavior in children and adolescents. Method: Case report. Case presentation: A 12-year-old boy who made a suicide attempt, was admitted to the emergency department at Centro Psíquico da Adolescência e Infância. After a period of irregular treatment, this child made a suicide attempt. As an inpatient, autism spectrum disorder with comorbid depressive disorder was diagnosed after longitudinal and systematic assessments of multidisciplinary team. Treatment was performed according to clinical issues. Discussion: This patient had a form of autism spectrum disorder on which core aspects were not so evident. In this child, there was an overlap between depressive symptoms and symptoms of autism spectrum disorder. Despite social isolation being present, this patient proved capable to disguising his condition using techniques of social and behavioral imitation and camouflage with the aim of adapting to social environment. Conclusion: This study emphasizes the importance of longitudinal evaluation and multidisciplinary assessment to differential diagnosis and appropriate treatment. It also opens a window for further investigations of a possible association between autism spectrum disorders and suicidal behavior in youth.

Context-dependent hyperactivity in syngap1a and syngap1b zebrafish models of SYNGAP1-related disorder.

SYNGAP1-related disorder (SYNGAP1-RD) is a prevalent genetic form of Autism Spectrum Disorder and Intellectual Disability (ASD/ID) and is caused by de novo or inherited mutations in one copy of the SYNGAP1 gene. In addition to ASD/ID, SYNGAP1 disorder is associated with comorbid symptoms including treatment-resistant-epilepsy, sleep disturbances, and gastrointestinal distress. Mechanistic links between these diverse symptoms and SYNGAP1 variants remain obscure, therefore, our goal was to generate a zebrafish model in which this range of symptoms can be studied. We used CRISPR/Cas9 to introduce frameshift mutations in the syngap1a and syngap1b zebrafish duplicates (syngap1ab) and validated these stable models for Syngap1 loss-of-function. Because SYNGAP1 is extensively spliced, we mapped splice variants to the two zebrafish syngap1a and b genes and identified mammalian-like isoforms. We then quantified locomotory behaviors in zebrafish syngap1ab larvae under three conditions that normally evoke different arousal states in wild-type larvae: aversive, high-arousal acoustic, medium-arousal dark, and low-arousal light stimuli. We show that CRISPR/Cas9 indels in zebrafish syngap1a and syngap1b produced loss-of-function alleles at RNA and protein levels. Our analyses of zebrafish Syngap1 isoforms showed that, as in mammals, zebrafish Syngap1 N- and C-termini are extensively spliced. We identified a zebrafish syngap1 α1-like variant that maps exclusively to the syngap1b gene. Quantifying locomotor behaviors showed that syngap1ab mutant larvae are hyperactive compared to wild-type but to differing degrees depending on the stimulus. Hyperactivity was most pronounced in low arousal settings, and hyperactivity was proportional to the number of mutant syngap1 alleles. Syngap1 loss-of-function mutations produce relatively subtle phenotypes in zebrafish compared to mammals. For example, while mouse Syngap1 homozygotes die at birth, zebrafish syngap1ab-/- survive to adulthood and are fertile, thus some aspects of symptoms in people with SYNGAP1-Related Disorder are not likely to be reflected in zebrafish. Our data support mutations in zebrafish syngap1ab as causal for hyperactivity associated with elevated arousal that is especially pronounced in low-arousal environments.

Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder

BackgroundMutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5−/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5−/y rats.MethodsTo allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology.ResultsOur results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5−/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5−/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses.ConclusionsOur data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity.LimitationsThis study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Developmental trajectories of GABAergic cortical interneurons are sequentially modulated by dynamic FoxG1 expression levels

GABAergic inhibitory interneurons, originating from the embryonic ventral forebrain territories, traverse a convoluted migratory path to reach the neocortex. These interneuron precursors undergo sequential phases of tangential and radial migration before settling into specific laminae during differentiation. Here, we show that the developmental trajectory of FoxG1 expression is dynamically controlled in these interneuron precursors at critical junctures of migration. By utilizing mouse genetic strategies, we elucidate the pivotal role of precise changes in FoxG1 expression levels during interneuron specification and migration. Our findings underscore the gene dosage-dependent function of FoxG1, aligning with clinical observations of FOXG1 haploinsufficiency and duplication in syndromic forms of autism spectrum disorders. In conclusion, our results reveal the finely tuned developmental clock governing cortical interneuron development, driven by temporal dynamics and the dose-dependent actions of FoxG1.

Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium

The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(−/−) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(−/−) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(−/−) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(−/−) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(−/−) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.

An inhibitory circuit-based enhancer of DYRK1A function reverses Dyrk1a-associated impairment in social recognition

Heterozygous mutations in the dual-specificity tyrosine phosphorylation-regulated kinase 1a (Dyrk1a) gene define a syndromic form of autism spectrum disorder. The synaptic and circuit mechanisms mediating DYRK1A functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin interneuron (PV IN) synapses by which DYRK1A recruits feedforward inhibition of CA3 and CA2 to promote social recognition. We employ genetic epistasis logic to identify a cytoskeletal protein, ABLIM3, as a synaptic substrate of DYRK1A. We demonstrate that Ablim3 downregulation in dentate granule cells of adult heterozygous Dyrk1a mice is sufficient to restore PV IN-mediated inhibition of CA3 and CA2 and social recognition. Acute chemogenetic activation of PV INs in CA3/CA2 of adult heterozygous Dyrk1a mice also rescued social recognition. Together, these findings illustrate how targeting DYRK1A synaptic and circuit substrates as "enhancers of DYRK1A function" harbors the potential to reverse Dyrk1a haploinsufficiency-associated circuit and cognition impairments.

Shank3 related muscular hypotonia is accompanied by increased intracellular calcium concentrations and ion channel dysregulation in striated muscle tissue.

Phelan-McDermid syndrome (PMS) is a syndromic form of Autism Spectrum Disorders (ASD) classified as a rare genetic neurodevelopmental disorder featuring global developmental delay, absent or delayed speech, ASD-like behaviour and neonatal skeletal muscle hypotonia. PMS is caused by a heterozygous deletion of the distal end of chromosome 22q13.3 or SHANK3 mutations. We analyzed striated muscles of newborn Shank3Δ11(-/-) animals and found a significant enlargement of the sarcoplasmic reticulum as previously seen in adult Shank3Δ11(-/-) mice, indicative of a Shank3-dependent and not compensatory mechanism for this structural alteration. We analyzed transcriptional differences by RNA-sequencing of muscle tissue of neonatal Shank3Δ11(-/-) mice and compared those to Shank3(+/+) controls. We found significant differences in gene expression of ion channels crucial for muscle contraction and for molecules involved in calcium ion regulation. In addition, calcium storage- [i.e., Calsequestrin (CSQ)], calcium secretion- and calcium-related signaling-proteins were found to be affected. By immunostainings and Western blot analyses we could confirm these findings both in Shank3Δ11(-/-) mice and PMS patient muscle tissue. Moreover, alterations could be induced in vitro by the selective downregulation of Shank3 in C2C12 myotubes. Our results emphasize that SHANK3 levels directly or indirectly regulate calcium homeostasis in a cell autonomous manner that might contribute to muscular hypotonia especially seen in the newborn.

BDNF content and catalase activity in the blood of children with autism spectrum disorders

BACKGROUND: With the increasing prevalence of autism spectrum disorders worldwide, it is relevant to study the mechanisms contributing to their development and progression. The participation of brain-derived neurotrophic factor and oxidative stress in the pathogenesis of the disease is considered, however, their role in this process remains unclear. The relationship between BDNF levels and oxidative stress in the blood of patients with autism spectrum disorders has not been studied.
 AIM: The aim was to evaluate the content of brain neurotrophic factor, BDNF, and catalase, an antioxidant defense enzyme, in children with various clinical forms of autism spectrum disorders.
 MATERIALS AND METHODS: BDNF content and catalase activity were assessed in the blood plasma of 78 children with autism spectrum disorders, including 41 patients with childhood autism, 19 children with atypical autism, 6 patients with Aspergers syndrome, and 12 patients with other general developmental disorders (with elements of autism). The control group consisted of 20 conditionally healthy children. The diagnosis was established in accordance with the ICD-10. The severity of disorders was determined using the Childhood Autism Rating Scale. The content of BDNF was evaluated using the method of enzyme immunoassay, catalase activity was determined by colorimetric method.
 RESULTS: The content of BDNF in blood plasma was reduced in children with autism spectrum disorders compared to its levels in control group subjects. BDNF levels depended on the clinical form of the disease: the content of BDNF was reduced in patients with childhood autism, atypical autism, Aspergers syndrome compared to control group subjects; in patients with atypical autism it is lower than in patients with childhood autism; BDNF levels in the group of patients with other general developmental disorders and in control group did not differ. The content of BDNF did not depend on gender, age and severity of autism spectrum disorders. A negative correlation was found between BDNF levels and the age of control group children. There were no differences in the activity of catalase in the blood of children with autism spectrum disorders and in control group. A positive correlation was found between BDNF levels and catalase activity in children with autism spectrum disorders and control group subjects.
 CONCLUSIONS: A decrease in the content of BDNF in the blood of children with autism spectrum disorders was revealed. Neurotrophin content differed in children with separate clinical forms of the disease. To varying degrees the decrease in BDNF levels in patients with childhood autism, atypical autism, Aspergers syndrome and the absence of changes in patients with other general developmental disorders compared with controls could be associated with a different contribution of neurotrophin to the pathogenesis of clinical forms of autism spectrum disorders. In children with autism spectrum disorders, there were no age-related changes in neurotrophin levels, while in healthy children a negative correlation was found between the content of BDNF and age. The absence of changes in the activity of catalase in the blood of children with autism spectrum disorders indicated the safety of the antioxidant defense system in terms of this indicator. The positive correlation between BDNF levels and catalase activity in the blood of patients with autism spectrum disorders and control group subjects reflected the protective role of neurotrophin from the damaging effects of oxidative stress.

TCF4 Mutations Disrupt Synaptic Function Through Dysregulation of RIMBP2 in Patient-Derived Cortical Neurons

BackgroundGenetic variation in the TCF4 (transcription factor 4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of autism spectrum disorder called Pitt-Hopkins syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models has been shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. MethodsTo model PTHS, we differentiated human cortical neurons from human induced pluripotent stem cells that were derived from patients with PTHS and neurotypical individuals. To identify pathophysiology and disease mechanisms, we assayed cortical neurons with whole-cell electrophysiology, Ca2+ imaging, multielectrode arrays, immunocytochemistry, and RNA sequencing. ResultsCortical neurons derived from patients with TCF4 mutations showed deficits in spontaneous synaptic transmission, network excitability, and homeostatic plasticity. Transcriptomic analysis indicated that these phenotypes resulted in part from altered expression of genes involved in presynaptic neurotransmission and identified the presynaptic binding protein RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. ConclusionsTaken together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.

Cochlear Nucleus Transcriptome of a Fragile X Mouse Model Reveals Candidate Genes for Hyperacusis.

Fragile X Syndrome (FXS) is a hereditary form of autism spectrum disorder. It is caused by a trinucleotide repeat expansion in the Fmr1 gene, leading to a loss of Fragile X Protein (FMRP) expression. The loss of FMRP causes auditory hypersensitivity: FXS patients display hyperacusis and the Fmr1- knock-out (KO) mouse model for FXS exhibits auditory seizures. FMRP is strongly expressed in the cochlear nucleus and other auditory brainstem nuclei. We hypothesize that the Fmr1-KO mouse has altered gene expression in the cochlear nucleus that may contribute to auditory hypersensitivity. RNA was isolated from cochlear nuclei of Fmr1-KO and WT mice. Using next-generation sequencing (RNA-seq), the transcriptomes of Fmr1-KO mice and WT mice (n = 3 each) were compared and analyzed using gene ontology programs. We identified 270 unique, differentially expressed genes between Fmr1-KO and WT cochlear nuclei. Upregulated genes (67%) are enriched in those encoding secreted molecules. Downregulated genes (33%) are enriched in neuronal function, including synaptic pathways, some of which are ideal candidate genes that may contribute to hyperacusis. The loss of FMRP can affect the expression of genes in the cochlear nucleus that are important for neuronal signaling. One of these, Kcnab2, which encodes a subunit of the Shaker voltage-gated potassium channel, is expressed at an abnormally low level in the Fmr1-KO cochlear nucleus. Kcnab2 and other differentially expressed genes may represent pathways for the development of hyperacusis. Future studies will be aimed at investigating the effects of these altered genes on hyperacusis. N/A Laryngoscope, 134:1363-1371, 2024.

Cognitive control in adults with high-functioning autism spectrum disorder: a study with event-related potentials.

Little is known about cognitive control in adults with high-functioning forms of autism spectrum disorder because previous research focused on children and adolescents. Cognitive control is crucial to monitor and readjust behavior after errors to select contextually appropriate reactions. The congruency effect and conflict adaptation are measures of cognitive control. Post-error slowing, error-related negativity and error positivity provide insight into behavioral and electrophysiological correlates of error processing. In children and adolescent with autism spectrum disorder deficits in cognitive control and error processing have been shown by changes in post-error slowing, error-related negativity and error positivity in the flanker task. We performed a modified Eriksen flanker task in 17 adults with high-functioning autism spectrum disorder and 17 healthy controls. As behavioral measures of cognitive control and error processing, we included reaction times and error rates to calculate congruency effects, conflict adaptation, and post-error slowing. Event-related potentials namely error-related negativity and error positivity were measured to assess error-related brain activity. Both groups of participants showed the expected congruency effects demonstrated by faster and more accurate responses in congruent compared to incongruent trials. Healthy controls exhibited conflict adaptation as they obtained performance benefits after incongruent trials whereas patients with autism spectrum disorder did not. The expected slowing in reaction times after errors was observed in both groups of participants. Individuals with autism spectrum disorder demonstrated enhanced electrophysiological error-processing compared to healthy controls indicated by increased error-related negativity and error positivity difference amplitudes. Our findings show that adults with high-functioning autism spectrum disorder do not show the expected upregulation of cognitive control in response to conflicts. This finding implies that previous experiences may have a reduced influence on current behavior in these patients which possibly contributes to less flexible behavior. Nevertheless, we observed intact behavioral reactions after errors indicating that adults with high-functioning autism spectrum disorder can flexibly adjust behavior in response to changed environmental demands when necessary. The enhancement of electrophysiological error-processing indicates that adults with high-functioning autism spectrum disorder demonstrate an extraordinary reactivity toward errors reflecting increased performance monitoring in this subpopulation of autism spectrum disorder patients.

Prospective One-Year Follow-Up of Sensory Processing in Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is caused by the loss (deletion) of a small portion of chromosome 22 in a region designated q13.3 (22q13.3 deletion). PMS is one of the most common genetic forms of autism spectrum disorder (ASD) in which sensory reactivity difficulties have been described on limited occasions. The objective of this study is to identify whether changes in sensory reactivity skills occur after one year of follow-up in a group of 44 participants diagnosed with PMS. All participants completed the Short Sensory Profile (SSP). Two-factor ANOVA tests were performed with repeated measures for the study of the evolution of the scores. Participants with PMS showed significant changes after one year of follow-up in sensory reactivity skills associated with tactile hyperreactivity (p = 0.003). The rest of the study variables did not show significant differences compared to the baseline assessment, showing definite differences associated with patterns of hypo-responsiveness and sensory seeking, low/weak energy, and difficulties in auditory filtering. Understanding the evolution of sensory reactivity skills can facilitate the adjustment to behavioral changes in people with PMS and design-targeted interventions to address sensory reactivity challenges.

Altered Expression and In Vivo Activity of mGlu5 Variant a Receptors in the Striatum of BTBR Mice: Novel Insights Into the Pathophysiology of Adult Idiopathic Forms of Autism Spectrum Disorders.

mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of "monogenic" forms of autism spectrum disorders (ASD), such as Fragile- X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects. Here, we studied the expression and function of mGlu5 receptors in the striatum of adult BTBR mice, which model idiopathic forms of ASD, and behavioral phenotype. Behavioral tests were associated with biochemistry analysis including qPCR and western blot for mRNA and protein expression. In vivo analysis of polyphosphoinositides hydrolysis was performed to study the mGlu5-mediated intracellular signaling in the striatum of adult BTBR mice under basal conditions and after MTEP exposure. Expression of mGlu5 receptors and mGlu5 receptor-mediated polyphosphoinositides hydrolysis were considerably high in the striatum of BTBR mice, sensitive to MTEP treatment. Changes in the expression of genes encoding for proteins involved in excitatory and inhibitory neurotransmission and synaptic plasticity, including Fmr1, Dlg4, Shank3, Brd4, bdnf-exon IX, Mef2c, and Arc, GriA2, Glun1, Nr2A, and Grm1, Grm2, GriA1, and Gad1 were also found. Behaviorally, BTBR mice showed high repetitive stereotypical behaviors, including self-grooming and deficits in social interactions. Acute or repeated injections with MTEP reversed the stereotyped behavior and the social interaction deficit. Similar effects were observed with the NMDA receptor blockers MK-801 or ketamine. These findings support a pivotal role of mGlu5 receptor abnormal expression and function in idiopathic ASD adult forms and unveil novel potential targets for therapy.

Early Signs of Autism and It’s Relation with Gestational Factors: An Urban Based Study in Bangladesh

A cross-sectional study was conducted to observe the prevalence autism spectrum disorders (ASD) and its correlation with gestational factors in country population between January and December of 2016. The study population was nursery school child aged 3-5 years whose parents were willing to participate in the study. In this study, the children are excluded whom already being identified as any forms of autism spectrum disorders. Convenient sampling technique was followed to select the samples from 47 schools of Uttara, Ashulia and Nikunjo area of Dhaka City Corporation and Tongi area of Gazipur City Corporation under Dhaka Division, Bangladesh. A total of 1000 children were recruited in the study. The research instrument was a semi-structured questionnaire based on Early Screening of Autistic Traits (ESAT) tool. Based on the diagnosis of the cases, parents were invited to another interview to fill out questionnaire related to some parental and gestational factors to assess the relationship with autism. The study found early signs of autism in 2.6% cases (26 in 1000), by using Early Screening of Autistic Traits (ESAT) questionnaire. Among the children having early signs of autism, history of normal birth weight was found more in term pregnancy (62.5%) than its preterm counterpart (60.0%). Growth parameter was higher in normal birth weight (68.8%) than low birth weight (60.0%). Similarly, growth parameter was also higher in children that are from 3rd gravida (75.0%) than that of 2nd gravida (66.7%) and 1st gravida (61.5%). Birth weight was also higher in >2 years birth spacing (60.0%) than that of <2 years (50.0%). Complication was more in home delivery (50.0%) than institutional delivery (20.8%). Birth injury happened more in home delivery than institutional delivery. Similarly, complication during delivery was higher in >2 years birth spacing (30.0%) than that of <2 years (0%), However, the difference was not significant statistically in any of the comparisons (P>0.05). Hence, no causal relation was found between autism and gestational factors. Bangladesh Med J. 2021 May; 50(2) : 9-14

Moral Agency, Rules, and Temporality in People Who Are Diagnosed With Mild Forms of Autism: In Defense of a Sentimentalist View.

The origin of moral agency is a much-debated issue. While rationalists or Kantians have argued that moral agency is rooted in reason, sentimentalists or Humeans have ascribed its origin to empathic feelings. This debate between rationalists and sentimentalists still stands with respect to persons with mental disorders, such as individuals diagnosed with mild forms of Autism Spectrum Disorder (ASD), without intellectual impairment. Individuals with ASD are typically regarded as moral agents, however their ability for empathy remains debated. The goal of this paper is to investigate the mechanisms of moral actions in people with ASD, by finding arguments for the origin of their moral actions, supporting either the sentimentalist or the rationalist view of the dispute. We propose to revisit the debate using Interpretative Phenomenological Analysis to study the autobiographies of individuals with High-Functioning Autism (HFA) and Asperger Syndrome (AS). While conducting the systematic analysis of 10 autobiographies, we re-examined both the rationalist and the sentimentalist positions, considering the links between empathic feelings and moral agency. The investigation of the temporal dimensions of emotional experiences, an aspect overlooked by previous research, indicated that individuals with ASD empathize with others, but in different ways as compared to neurotypicals. A relationship between emotional experience and the type of moral agency exhibited by individuals with forms of ASD was established. As a consequence, our analyses support the sentimentalist stance on moral action.

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Mutations or deletions of the SHANK3 gene are causative for Phelan–McDermid syndrome (PMDS), a syndromic form of autism spectrum disorders (ASDs). We analyzed Shank3Δ11(−/−) mice and organoids from PMDS individuals to study effects on myelin. SHANK3 was found to be expressed in oligodendrocytes and Schwann cells, and MRI analysis of Shank3Δ11(−/−) mice revealed a reduced volume of the corpus callosum as seen in PMDS patients. Myelin proteins including myelin basic protein showed significant temporal and regional differences with lower levels in the CNS but increased amounts in the PNS of Shank3Δ11(−/−) animals. Node, as well as paranode, lengths were increased and ultrastructural analysis revealed region-specific alterations of the myelin sheaths. In PMDS hiPSC-derived cerebral organoids we observed an altered number and delayed maturation of myelinating cells. These findings provide evidence that, in addition to a synaptic deregulation, impairment of myelin might profoundly contribute to the clinical manifestation of SHANK3 deficiency.

De Novo Large Deletion Leading to Fragile X Syndrome.

Fragile X syndrome (FXS) is the most frequent cause of X-linked inherited intellectual disabilities (ID) and the most frequent monogenic form of autism spectrum disorders. It is caused by an expansion of a CGG trinucleotide repeat located in the 5′UTR of the FMR1 gene, resulting in the absence of the fragile X mental retardation protein, FMRP. Other mechanisms such as deletions or point mutations of the FMR1 gene have been described and account for approximately 1% of individuals with FXS. Here, we report a 7-year-old boy with FXS with a de novo deletion of approximately 1.1 Mb encompassing several genes, including the FMR1 and the ASFMR1 genes, and several miRNAs, whose lack of function could result in the observed proband phenotypes. In addition, we also demonstrate that FMR4 completely overlaps with ASFMR1, and there are no sequencing differences between both transcripts (i.e., ASFMR1/FMR4 throughout the article).

Factors associated with age of diagnosis in children with autism spectrum disorders: Report from a French cohort.

Autism spectrum disorder is an early onset neurodevelopmental disorder and diagnosis can be made as early as 18 months of age. Early diagnosis of autism spectrum disorder is critical as it leads to early intervention. Age of autism spectrum disorder diagnosis has been linked to the child profile as autism spectrum disorder is characterized by strong heterogeneity, but is also influenced by socio-economic factors. There is paucity of data on age of diagnosis of autism spectrum disorder in France. We therefore examined the age of autism spectrum disorder diagnosis in 554 children and adolescents enrolled in the ELENA cohort study with respect to the influences of child profile, family antecedents, and socio-economic factors. The mean age of diagnosis was 4.9 years (±2.8 years). Early diagnosis, before 3 years of age, was related to the co-occurrence of intellectual disability, higher autism spectrum disorder symptom severity, and lower communicative abilities. Children in low socio-economic status families tended to have an earlier diagnosis, but these children also had greater degree of intellectual impairment compared to children in high socio-economic status families. The age of autism spectrum disorder diagnosis was not associated with the presence of an older sibling with autism spectrum disorder. The observed current trend of an inverse relationship between socio-economic status and age of diagnosis of autism spectrum disorder suggests equitable access to autism spectrum disorder services in France where health coverage is universal and free. Better screening of more subtle/less severe forms of autism spectrum disorder is needed, as well as further assessment of the link between the co-occurrence of autism spectrum disorder and intellectual impairment in children in lower socio-economic status families.