1. Davoudi S, Rahdar M, Hosseinmardi N, Behzadi G, Janahmadi M. Chronic inhibition of astrocytic aquaporin-4 induces autistic-like behavior in control rat offspring similar to maternal exposure to valproic acid. Physiology & behavior. 2023: 114286.

Social communication and interaction deficits, memory impairment, and anxiety-like behavior are characterized in many people identified with autism spectrum disorder (ASD). A thorough understanding of the specific aspects that contribute to the deficiencies associated with ASD can aid research into the etiology of the disorder while also providing targets for more effective intervention. As part of the ASD pathophysiology, alterations in synaptogenesis and abnormal network connections were seen in high-order brain areas, which control social behavior and communication. The early emergence of microglia during nervous system development may contribute to synaptic dysfunction and the pathobiology of ASD. Since aquaporin-4 (AQP4) appears to be required for the basic procedures of synapse activation, certain behavioral and cognitive impairments as well as disturbance in water homeostasis might likely arise from AQP4 deficiency. Here, through the measurement of the water content of the hippocampus and behavioral experiments we aim to explore the contribution of astrocytic AQP4 to the autism-like behavior induced by prenatal valproic acid (VPA) exposure and whether inhibition of AQP4 per se can induce autistic-like behavior in control rats. Microinjection of TGN-020 (10µM, i.c.v), a specific AQP4 inhibitor, for 7 successive days before behavioral tasks from postnatal day 28 to 35 revealed that inhibition of AQP4 in the control offspring caused lower social interaction and locomotor activity, higher anxiety, and decreased ability to recognize novel objects, very similar to the behavioral changes observed in offspring prenatally exposed to VPA. However, VPA-exposed offspring treated with TGN-020, showed no further remarkable behavioral impairments than those detected in the autistic-like rats. Furthermore, both control offspring treated with TGN-020 and offspring exposed to VPA had a considerable accumulation of water in their hippocampi. But AQP4 inhibition did not affect the water status of the autistic-like rats. The findings of this study revealed that control offspring exhibited similar hippocampal water retention and behavioral impairments that were observed in maternal VPA-exposed offspring following inhibition of astrocytic AQP4, whereas, in autistic-like rats, it did not produce any significant change in water content and behaviors. Findings suggest that AQP4 deficiency could be associated with autistic disorder and may be a potential pharmaceutical target for treating autism in the future.

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2. Di Menna L, Orlando R, D’Errico G, Ginerete RP, Machaczka A, Bonaccorso CM, Arena A, Spatuzza M, Celli R, Alborghetti M, Ciocca E, Zuena AR, Scioli MR, Bruno V, Battaglia G, Nicoletti F, Catania MV. Blunted type-5 metabotropic glutamate receptor-mediated polyphosphoinositide hydrolysis in two mouse models of monogenic autism. Neuropharmacology. 2023: 109642.

The involvement of the mGlu5 receptors in the pathophysiology of several forms of monogenic autism has been supported by numerous studies following the seminal observation that mGlu5 receptor-dependent long-term depression was enhanced in the hippocampus of mice modeling the fragile-X syndrome (FXS). Surprisingly, there are no studies examining the canonical signal transduction pathway activated by mGlu5 receptors (i.e. polyphosphoinositide – PI – hydrolysis) in mouse models of autism. We have developed a method for in vivo assessment of PI hydrolysis based on systemic injection of lithium chloride followed by treatment with the selective mGlu5 receptor PAM, VU0360172, and measurement of endogenous inositolmonophosphate (InsP) in brain tissue. Here, we report that mGlu5 receptor-mediated PI hydrolysis was blunted in the cerebral cortex, hippocampus, and corpus striatum of Ube3a(m-/p+) mice modeling Angelman syndrome (AS), and in the cerebral cortex and hippocampus of fmr1 knockout mice modeling FXS. In vivo mGlu5 receptor-mediated stimulation of Akt on threonine 308 was also blunted in the hippocampus of FXS mice. These changes were associated with a significant increase in cortical and striatal Homer1 levels and striatal mGlu5 receptor and Gαq levels in AS mice, and with a reduction in cortical mGlu5 receptor and hippocampal Gαq levels, and an increase in cortical phospholipase-Cβ and hippocampal Homer1 levels in FXS mice. This is the first evidence that the canonical transduction pathway activated by mGlu5 receptors is down-regulated in brain regions of mice modeling monogenic autism.

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3. Hamdan SZ, Davis M, Faig W, Guthrie W, Yerys BE, Wallis KE. Lower Completion of Depression Screening and Higher Positivity Among Autistic Adolescents Across a Large Pediatric Primary Care Network. Academic pediatrics. 2023.

OBJECTIVE: To examine rates of depression screening and positivity among autistic adolescents where electronic depression screening is administered universally; to compare rates between autistic and non-autistic youth; and to explore sociodemographic and clinical factors associated with screening completion and results. METHODS: We conducted a retrospective cohort study comparing 12-17-year-old autistic and non-autistic adolescents presenting for well-child care in a large pediatric primary care network between November 2017 and January 2019 (N=60,181). Sociodemographic and clinical data, including PHQ-9-M completion status and results, were extracted digitally from the electronic health record and compared between autistic and non-autistic youth. Logistic regression explored the relationship between sociodemographic and clinical factors and screen completion and results, stratified by autism diagnosis. RESULTS: Autistic adolescents were significantly less likely to have a completed depression screen compared to non-autistic adolescents [67.0% versus 78.9%, Odds Ratio (OR)=0.54, p<0.01]. Among those with a completed screen, a higher percentage of autistic youths screened positive for depression (39.1% versus 22.8%; OR=2.18, p<0.01,) and suicidal ideation/behavior (13.4% versus 6.8%; OR=2.13, p<0.01). Factors associated with screening completion and positivity differed between autistic and non-autistic groups. CONCLUSION: Autistic adolescents were less likely to have a completed depression screen when presenting for well-child care. However, when screened, they were more likely to endorse depression and suicide risk. This suggests disparities in depression screening and risk among autistic youth compared to non-autistic youth. Additional research should evaluate the source of these disparities, explore barriers to screening, and examine longitudinal outcomes of positive results among this population. WHAT'S NEW: We describe the current status of depression screening among autistic adolescents compared to their non-autistic peers in a primary care network with well-established universal electronic screening, and the demographic and clinical factors associated with screening completion and positivity in both groups.

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4. Masters EC, Antshel KM, Kates WR, Russo N. Brief Report: Sensory Features Associated with Autism After Controlling for ADHD Symptoms. Journal of autism and developmental disorders. 2023.

BACKGROUND: Sensory processing differences are reported both in children with ADHD and in children with autism. Given the substantial overlap between autism and ADHD, the current study examined which sensory features were uniquely predictive of autistic traits after controlling for ADHD symptoms, age, IQ, and sex in a sample of children and adolescents with autism aged 6-17 years. METHODS: The sample included 61 children and adolescents with autism. The Sensory Profile was used to examine Dunn’s quadrant model (seeking, sensitivity, avoiding, registration), ADHD symptoms were measured using hyperactivity and attention problems BASC-2 T-scores, and autistic traits were measured using the AQ. RESULTS: After controlling for age, IQ, sex, and ADHD symptoms, Dunn’s sensitivity quadrant predicted autistic traits. CONCLUSIONS: Findings provide insight into the phenotype of autism and ADHD. Sensory sensitivity may be unique to autism over and above elevated ADHD symptoms that are commonly seen in this population.

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5. Riek NT, Susam BT, Hudac CM, Conner CM, Akcakaya M, Yun J, White SW, Mazefsky CA, Gable PA. Feedback Related Negativity Amplitude is Greatest Following Deceptive Feedback in Autistic Adolescents. Journal of autism and developmental disorders. 2023.

The purpose of this study is to investigate if feedback related negativity (FRN) can capture instantaneous elevated emotional reactivity in autistic adolescents. A measurement of elevated reactivity could allow clinicians to better support autistic individuals without the need for self-reporting or verbal conveyance. The study investigated reactivity in 46 autistic adolescents (ages 12-21 years) completing the Affective Posner Task which utilizes deceptive feedback to elicit distress presented as frustration. The FRN event-related potential (ERP) served as an instantaneous quantitative neural measurement of emotional reactivity. We compared deceptive and distressing feedback to both truthful but distressing feedback and truthful and non-distressing feedback using the FRN, response times in the successive trial, and Emotion Dysregulation Inventory (EDI) reactivity scores. Results revealed that FRN values were most negative to deceptive feedback as compared to truthful non-distressing feedback. Furthermore, distressing feedback led to faster response times in the successive trial on average. Lastly, participants with higher EDI reactivity scores had more negative FRN values for non-distressing truthful feedback compared to participants with lower reactivity scores. The FRN amplitude showed changes based on both frustration and reactivity. The findings of this investigation support using the FRN to better understand emotion regulation processes for autistic adolescents in future work. Furthermore, the change in FRN based on reactivity suggests the possible need to subgroup autistic adolescents based on reactivity and adjust interventions accordingly.

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6. Wang J, Yu J, Wang M, Zhang L, Yang K, Du X, Wu J, Wang X, Li F, Qiu Z. Discovery and validation of novel genes in a large Chinese ASD cohort. Biological psychiatry. 2023.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that causes impairments in social communication and stereotypical behaviors, often accompanied by developmental delay or intellectual disabilities (DD/ID). A growing body of evidence suggests that ASD is highly heritable, and genetic studies have defined numerous risk genes. However, most studies have been conducted with individuals of European and Hispanic ancestry, and there is a lack of genetic analyses of ASD in the East Asian population. METHODS: We performed whole-exome sequencing on 772 Chinese ASD trios and combined the data with a previous study of 369 Chinese ASD trios, identifying de novo variants in 1141 ASD trios. We used single-cell RNA sequencing analysis to identify the cell types in which ASD-related genes were enriched. Additionally, we validated the function of a candidate high-functioning autism gene in mouse models using mouse genetics. RESULTS: Our findings showed that ASD without DD/ID carried fewer disruptive de novo variants than ASD with DD/ID. Moreover, we identified nine novel ASD candidate genes that were not present in the current ASD gene database. We further validated one such novel ASD candidate gene, SLC35G1, by showing that mice harboring a heterozygous deletion of Slc35g1 exhibited defects in interactive social behaviors. CONCLUSIONS: Our work nominates novel ASD candidate genes and emphasizes the importance of genome-wide genetic studies in ASD cohorts of different ancestries to reveal the comprehensive genetic architecture of ASD.

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