1. Cervantes PE, Li A, Sullivan KA, Seag DEM, Baroni A, Horwitz SM. Assessing and Managing Suicide Risk in Autistic Youth: Findings from a Clinician Survey in a Pediatric Psychiatric Emergency Setting. Journal of autism and developmental disorders. 2022.

Suicidal thoughts and behaviors (STB) and emergency department (ED) utilization are prevalent in autistic youth. The current study surveyed clinicians in a pediatric psychiatric ED to examine differences in attitudes on suicide-related care for autistic and non-autistic patient populations. While clinicians rated addressing STB in ASD as important and adaptations to care as necessary, less than half identified ASD as a suicide risk factor and confidence ratings were significantly lower for autistic patients. Previous ASD training predicted confidence and accounted for approximately 25% of the variance in confidence scores. Findings highlight the urgency to develop and disseminate ED clinician training, and address the lack of validated assessment tools, adapted suicide prevention practices, and evidence-based treatments for STB in autistic youth.

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2. Despang P, Salamon S, Breitenkamp A, Kuzmenkina E, Matthes J. Inhibitory effects on L- and N-type calcium channels by a novel Ca(V)β(1) variant identified in a patient with autism spectrum disorder. Naunyn-Schmiedeberg’s archives of pharmacology. 2022; 395(4): 459-70.

Voltage-gated calcium channel (VGCC) subunits have been genetically associated with autism spectrum disorders (ASD). The properties of the pore-forming VGCC subunit are modulated by auxiliary β-subunits, which exist in four isoforms (Ca(V)β(1-4)). Our previous findings suggested that activation of L-type VGCCs is a common feature of Ca(V)β(2) subunit mutations found in ASD patients. In the current study, we functionally characterized a novel Ca(V)β(1b) variant (p.R296C) identified in an ASD patient. We used whole-cell and single-channel patch clamp to study the effect of Ca(V)β(1b_R296C) on the function of L- and N-type VGCCs. Furthermore, we used co-immunoprecipitation followed by Western blot to evaluate the interaction of the Ca(V)β(1b)-subunits with the RGK-protein Gem. Our data obtained at both, whole-cell and single-channel levels, show that compared to a wild-type Ca(V)β(1b), the Ca(V)β(1b_R296C) variant inhibits L- and N-type VGCCs. Interaction with and modulation by the RGK-protein Gem seems to be intact. Our findings indicate functional effects of the Ca(V)β(1b_R296C) variant differing from that attributed to Ca(V)β(2) variants found in ASD patients. Further studies have to detail the effects on different VGCC subtypes and on VGCC expression.

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3. Fernando MB, Brennand KJ. Quickly moving too slowly: Interneuron migration in Timothy Syndrome. Cell stem cell. 2022; 29(2): 181-3.

Aberrant migration of GABAergic interneurons during cortical neurodevelopment is implicated in Timothy Syndrome, yet the underlying mechanisms remain elusive. In this issue of Cell Stem Cell, Birey et al. model developing brain circuitry using « assembloids » from patients, characterizing a bimodal mechanism of mechano-chemically driven interneuron migration inefficiencies.

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4. Lemprière S. Novel oxytocin spray is beneficial in ASD. Nature reviews Neurology. 2022; 18(3): 127.

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5. Narasimhan U, Janakiraman A, Puskur D, Anitha FS, Paul SFD, Koshy T. Case Report: A Disease Phenotype of Rett Syndrome and Neurofibromatosis Resulting from A Bilocus Variant Combination. Journal of autism and developmental disorders. 2022.

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6. Nussinov R, Tsai CJ, Jang H. Allostery, and how to define and measure signal transduction. Biophysical chemistry. 2022; 283: 106766.

Here we ask: What is productive signaling? How to define it, how to measure it, and most of all, what are the parameters that determine it? Further, what determines the strength of signaling from an upstream to a downstream node in a specific cell? These questions have either not been considered or not entirely resolved. The requirements for the signal to propagate downstream to activate (repress) transcription have not been considered either. Yet, the questions are pivotal to clarify, especially in diseases such as cancer where determination of signal propagation can point to cell proliferation and to emerging drug resistance, and to neurodevelopmental disorders, such as RASopathy, autism, attention-deficit/hyperactivity disorder (ADHD), and cerebral palsy. Here we propose a framework for signal transduction from an upstream to a downstream node addressing these questions. Defining cellular processes, experimentally measuring them, and devising powerful computational AI-powered algorithms that exploit the measurements, are essential for quantitative science.

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7. Rao SR, Kostic A, Baillargeon P, Fernandez-Vega V, de Anda MR, Fletcher K, Shumate J, Scampavia L, Buxbaum JD, Spicer TP. Screening for modulators of autism spectrum disorder using induced human neurons. SLAS discovery : advancing life sciences R & D. 2022; 27(2): 128-39.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder. There are no drugs to treat the core symptoms. De novo mutations often play an important role in ASD and multiple high-risk loci have been identified in the last decade. These mutations range from copy number variants to small insertion/deletion and single nucleotide variants. Large-scale exome sequencing has identified over 100 risk genes that are associated with ASD. Both etiological heterogeneity and unavailability of human neurons remain major hurdles in understanding the pathophysiology of ASD and testing of new drug candidates. Hence, the most achievable and relevant model to screen for potential drugs is human neurons from inducible pluripotent stem cells (iPSCs), including those from individuals with genetic mutations. In this study, we tested stem cells from individuals carrying mutations in ADNP, FOXP1 or SHANK3. They were scaled and reprogrammed to glutamatergic neurons and assessed for the effects of their specific mutations on neurite outgrowth. High Content Analysis allowed us to observe phenotypic differences between ASD neurons compared to controls, in terms of neuron number, neurite number and neurite length per neuron. Further, neurons were derived from both patient derived and genetically modified iPSCs with DDX3X mutation which were tested against 5088 drug like compounds. We assessed individual compound effects on the induced neurons to determine if they elicited changes that would indicate neurite growth (neuroprotection) or, alternatively, reduce outgrowth and hence appear neurotoxic. This report includes all methods, phenotypic outcomes, and results for the largest ASD small molecule screening effort done to date.

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8. Rosen TE, Pickard K, Ponomaryova A, Kerns CM, Reaven J. From Clinic to Classroom: Two Case Studies of Youth With ASD and Anxiety From the School-Based Facing Your Fears Program. Journal of cognitive psychotherapy. 2022; 36(1): 24-41.

Cognitive behavioral therapy (CBT) is considered best practice for treating anxiety in youth with autism spectrum disorder (ASD) in clinic settings. However, there is significant need to translate CBT into school settings. This paper presents two case illustrations of students who participated in the Facing Your Fears: School-Based program (FYF-SB), a manualized, group CBT intervention for anxiety in ASD, adapted for delivery in schools by interdisciplinary school providers. Students showed improvement in anxiety across multiple domains following intervention, according to clinical interview and parent- and self-report. These outcomes suggest that anxious youth with ASD can benefit from CBT delivered by interdisciplinary school providers. Importantly, decreases in anxiety symptoms were evident in domains that were not explicitly targeted during intervention. Overall, these case illustrations help frame areas of future research, including examining how treatment gains may generalize across anxiety domains as well as whether corresponding improvement in school functioning occurs.

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9. Schröder CM, Broquère MA, Claustrat B, Delorme R, Franco P, Lecendreux M, Tordjman S. [Therapeutic approaches for sleep and rhythms disorders in children with ASD]. L’Encephale. 2022.

Sleep disturbances are extremely common (40-86%) in children and adolescents, especially those with autism spectrum disorders (ASD) and are often among the first symptoms identified by parents at a very early stage of their child’s development. These abnormalities are among the main parental concerns when having a child with ASD and have a significant impact on the quality of life of patients, their parents, and more broadly their siblings. Sleep disorders are essentially abnormalities of the sleep-wake rhythm – primarily sleep onset insomnia or nocturnal awakenings (with difficulty falling back to sleep). These disturbances can be accompanied by other sleep disorders, requiring notably a systematic elimination of the presence of a sleep apnea or restless legs syndrome – to ensure a personalized and efficient therapeutic approach. Physiologically, the determinants of these sleep disorders are poorly understood, even though several studies point to a significant decrease in melatonin synthesis in people with ASD. Melatonin is a hormone that facilitates falling asleep and maintaining sleep and is also involved in the endogenous synchronization of internal biological clocks. However, the causal factors of this decrease in melatonin synthesis are largely unknown, involving to a small extent the genes involved in melatonin synthesis pathway. The treatment of sleep disorders is relatively systematic: after eliminating other specific sleep disorders associated with the complaint of insomnia, as well as other possible associated comorbidities (such as seizures), a global and graduated therapeutic approach must be put in place. This treatment will be non-pharmacological as a first line, then pharmacological as a second line. A number of non-pharmacological treatment strategies for sleep disorders in typically developing children and adolescents, as well as those with ASD, have been shown to be effective. This treatment requires a combination of: 1) parental education to promote sleep development; 2) setting up bedtime rituals adapted to the child’s age and particularities; 3) specific behavioral strategies including bedtime fading, gradual extinction and positive reinforcement of adapted behaviors. It is very essential that the parents are accompanied throughout this therapy. Sleep hygiene and behavioral care must also take into consideration the important role of the zeitgebers of sleep-wake rhythms, i.e. the external environmental factors involved in the synchronization of the biological clocks: regular exposure to light at adapted times, regular meal and wake-up times, social activities and times for going to school. The evidence for the effectiveness of behavioral interventions in the treatment of behavioral insomnia in the typical developmental child is strong, since 94% of children show clinically significant improvements in nighttime sleepiness and waking. By contrast, only about 25% of children with ASD are improved by an approach combining sleep hygiene and behavioral therapy. Melatonin has a special and prominent place in the drug management of sleep disorders associated with ASD. Several clinical trials have shown that melatonin is effective in treating sleep disorders in patients with ASD. This work led to the European Medicines Agency (EMA) granting marketing authorization in September 2018 for a sustained-release paediatric melatonin molecule (Slenyto®). This synthetic molecule is a prolonged release melatonin (PRM) which mimics the physiological pharmacokinetic and secretory characteristics of endogenous melatonin, having a very short blood half-life and prolonged secretion for several hours during the night. A recent study evaluated the efficacy and safety of pediatric PRM (mini-tablets) in 125 children, aged 2 to 17.5 years with mainly ASD. After 15 days on placebo, the children were randomized into two parallel groups, PRM or placebo in a double-blind design for 13 weeks. At endpoint, total sleep time was increased by an average of 57.5 minutes on PRM and only 9.14 minutes on placebo (P=0.034). This difference between the two groups was already significant after three weeks of treatment (P=0.006). Sleep latency was also improved in the PRM group (-39.6 minutes) compared to placebo (-12.51 minutes) (P=0.01). Consolidated sleep duration (uninterrupted by awakenings) was improved by 77.9 minutes for the PRM group and only 25.4 minutes for the placebo group (P<0.001). PRM was well tolerated, the most frequent side effects being headache and daytime drowsiness at the same level with PRM or placebo. In addition, the acceptability by the children for swallowing the mini-tablets was excellent (100% compliance). The efficacy and tolerability of PRM was maintained over the medium and long term in the open phase, over a total study duration of 2 years.

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10. Tseng CJ, McDougle CJ, Hooker JM, Zürcher NR. Epigenetics of Autism Spectrum Disorder: Histone Deacetylases. Biological psychiatry. 2021.

The etiology of autism spectrum disorder (ASD) remains unknown, but gene-environment interactions, mediated through epigenetic mechanisms, are thought to be a key contributing factor. Prenatal environmental factors have been shown to be associated with both increased risk of ASD and altered histone deacetylases (HDACs) or acetylation levels. The relationship between epigenetic changes and gene expression in ASD suggests that alterations in histone acetylation, which lead to changes in gene transcription, may play a key role in ASD. Alterations in the acetylome have been demonstrated for several genes in ASD, including genes involved in synaptic function, neuronal excitability, and immune responses, which are mechanisms previously implicated in ASD. We review preclinical and clinical studies that investigated HDACs and autism-associated behaviors and discuss risk genes for ASD that code for proteins associated with HDACs. HDACs are also implicated in neurodevelopmental disorders with a known genetic etiology, such as 15q11-q13 duplication and Phelan-McDermid syndrome, which share clinical features and diagnostic comorbidities (e.g., epilepsy, anxiety, and intellectual disability) with ASD. Furthermore, we highlight factors that affect the behavioral phenotype of acetylome changes, including sensitive developmental periods and brain region specificity in the context of epigenetic programming.

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11. Wang CG, Feng C, Zhou ZR, Cao WY, He DJ, Jiang ZL, Lin F. Imbalanced Gamma-band Functional Brain Networks of Autism Spectrum Disorders. Neuroscience. 2022.

Resting gamma-band brain networks are known as an inhibitory component in functional brain networks. Although autism spectrum disorder (ASD) is considered as with imbalanced brain networks, the inhibitory component remains not fully explored. The study reported 10 children with ASD and 10 typically-developing (TD) controls. The power spectral density analysis of the gamma-band signal in the cerebral cortex was performed at the source level. The normalized phase transfer entropy values (nPTEs) were calculated to construct brain connectivity. Gamma-band activity of the ASD group was lower than the TD children. The significantly inhibited brain regions were mainly distributed in the bilateral frontal and temporal lobes. Connectivity analysis showed alterations in the connections from key nodes of the social brain network. The behavior assessments in the ASD group revealed a significantly positive correlation between the total score of Childhood Autism Rating Scale and the regional nPTEs of the right transverse temporal gyrus. Our results provide strong evidence that the gamma-band brain networks of ASD children have a lower level of brain activities and different distribution of information flows. Clinical meanings of such imbalances of both activity and connectivity were also worthy of further explorations.

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