1. Hacohen-Kleiman G, Yizhar-Barnea O, Touloumi O, Lagoudaki R, Avraham KB, Grigoriadis N, Gozes I. {{Atypical Auditory Brainstem Response and Protein Expression Aberrations Related to ASD and Hearing Loss in the Adnp Haploinsufficient Mouse Brain}}. {Neurochemical research}. 2019.
Autism is a wide spread neurodevelopmental disorder with growing morbidity rates, affecting more boys than girls worldwide. Activity-dependent neuroprotective protein (ADNP) was recently recognized as a leading gene accounted for 0.17% of autism spectrum disorder (ASD) cases globally. Respectively, mutations in the human ADNP gene (ADNP syndrome), cause multi-system body dysfunctions with apparent ASD-related traits, commencing as early as childhood. The Adnp haploinsufficient (Adnp(+/-)) mouse model was researched before in relations to Alzheimer’s disease and autism. Adnp(+/-) mice suffer from deficient social memory, vocal and motor impediments, irregular tooth eruption and short stature, all of which corresponds with reported phenotypes in patients with the ADNP syndrome. Recently, a more elaborated description of the ADNP syndrome was published, presenting impediments such as hearing disabilities in > 10% of the studied children. Irregular auditory brainstem response (ABR) has been connected to ASD-related cases and has been suggested as a potential hallmark for autism, allowing diagnosis of ASD risk and early intervention. Herein, we present detriment hearing in the Adnp(+/-) mice with atypical ABR and significant protein expression irregularities that coincides with ASD and hearing loss studies in the brain.
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2. Hadad BS, Schwartz S, Binur N. {{Reduced perceptual specialization in autism: Evidence from the other-race face effect}}. {Journal of experimental psychology General}. 2019.
Emerging accounts of autism suggest that flexible and broadly tuned perceptual representations, presumably resulting from reduced specialization, may underlie atypical perception. Here, we examined the other-race effect (ORE) to study face processing specialization arising from specific experience with own-race faces. Face discrimination was tested for own- and other-race faces in typically developed individuals and in individuals with autism spectrum disorder (ASD). For each race, faces were morphed to vary discrimination difficulty, and orientation was manipulated to examine inversion effects. The ASD group displayed overall lower sensitivity and reduced inversion effects in processing faces. Importantly, the processing advantage for own-race faces was substantially smaller in this group, resulting specifically from the reduced specialization for the own-race faces. Moreover, the typical larger inversion effect for Caucasian faces was not observed in the ASD group; sensitivity to orientation was smaller and equivalent for the two face races. These more broadly tuned representations in autism may account for the overall weaker representations of faces and suggest, more broadly, that a failure in perceptual specialization may underlie atypical perception in autism. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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3. Hegarty JP, 2nd, Pegoraro LFL, Lazzeroni LC, Raman MM, Hallmayer JF, Monterrey JC, Cleveland SC, Wolke ON, Phillips JM, Reiss AL, Hardan AY. {{Genetic and environmental influences on structural brain measures in twins with autism spectrum disorder}}. {Mol Psychiatry}. 2019.
Atypical growth patterns of the brain have been previously reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on brain development. Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) were recruited to participate in this study. T1-weighted MRIs (n = 164) were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across diagnostic groups. ACE modeling was also completed. Structural brain measures, including cerebral and cerebellar gray matter (GM) and white matter (WM) volume, surface area, and cortical thickness, were primarily influenced by genetic factors in TD twins; however, mean curvature appeared to be primarily influenced by environmental factors. Similarly, genetic factors accounted for the majority of variation in brain size in twins with ASD, potentially to a larger extent regarding curvature and subcortical GM; however, there were also more environmental contributions in twins with ASD on some structural brain measures, such that cortical thickness and cerebellar WM volume were primarily influenced by environmental factors. These findings indicate potential neurobiological outcomes of the genetic and environmental risk factors that have been previously associated with ASD and, although preliminary, may help account for some of the previously outlined neurobiological heterogeneity across affected individuals. This is especially relevant regarding the role of genetic and environmental factors in the development of ASD, in which certain brain structures may be more sensitive to specific influences.
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4. Hessl D, Harvey D, Sansone S, Crestodina C, Chin J, Joshi R, Hagerman RJ, Berry-Kravis E. {{Effects of mavoglurant on visual attention and pupil reactivity while viewing photographs of faces in Fragile X Syndrome}}. {PLoS One}. 2019; 14(1): e0209984.
BACKGROUND: Numerous preclinical studies have supported the theory that enhanced activation of mGluR5 signaling, due to the absence or reduction of the FMR1 protein, contributes to cognitive and behavioral deficits in patients with fragile X syndrome (FXS). However multiple phase 2 controlled trials in patients with FXS have failed to demonstrate efficacy of compounds that negatively modulate mGluR5, including two phase 2b randomized controlled trials (RCT) of mavoglurant (AFQ056, Novartis Pharma AG), when the primary measures of interest were behavioral ratings. This has cast some doubt onto the translation of the mGluR5 theory from animal models to humans with the disorder. METHODS: We evaluated social gaze behavior-a key phenotypic feature of the disorder-and sympathetic nervous system influence on pupil size using a previously-validated eye tracking paradigm as a biobehavioral probe, in 57 adolescent or adult patients with FXS at baseline and following three months of blinded treatment with one of three doses of mavoglurant or placebo, within the context of the AFQ056 RCTs. RESULTS: Patients with FXS treated with mavoglurant demonstrated increased total absolute looking time and number of fixations to the eye region while viewing human faces relative to baseline, and compared to those treated with placebo. In addition, patients had greater pupil reactivity to faces relative to baseline following mavoglurant treatment compared to placebo. DISCUSSION: The study shows that negative modulation of mGluR5 activity improves eye gaze behavior and alters sympathetically-driven reactivity to faces in patients with FXS, providing preliminary evidence of this drug’s impact on behavior in humans with the disorder.
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5. Kappel DB, Schuch JB, Rovaris DL, da Silva BS, Muller D, Breda V, Teche SP, R SR, Schuler-Faccini L, Rohde LA, Grevet EH, Bau CHD. {{ADGRL3 rs6551665 as a Common Vulnerability Factor Underlying Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder}}. {Neuromolecular medicine}. 2019.
Neurodevelopmental disorders are prevalent, frequently occur in comorbidity and share substantial genetic correlation. Previous evidence has suggested a role for the ADGRL3 gene in Attention-Deficit/Hyperactivity Disorder (ADHD) susceptibility in several samples. Considering ADGRL3 functionality in central nervous system development and its previous association with neurodevelopmental disorders, we aimed to assess ADGRL3 influence in early-onset ADHD (before 7 years of age) and Autism Spectrum Disorder (ASD). The sample comprises 187 men diagnosed with early-onset ADHD, 135 boys diagnosed with ASD and 468 male blood donors. We tested the association of an ADGRL3 variant (rs6551665) with both early-onset ADHD and ASD susceptibility. We observed significant associations between ADGRL3-rs6551665 on ADHD and ASD susceptibilities; we found that G-carriers were at increased risk of ADHD and ASD, in accordance with previous studies. The overall evidence from the literature, corroborated by our results, suggests that ADGRL3 might be involved in brain development, and genetic modifications related to it might be part of a shared vulnerability factor associated with the underlying neurobiology of neurodevelopmental disorders such as ADHD and ASD.
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6. Morgan BR, Ibrahim GM, Vogan VM, Leung RC, Lee W, Taylor MJ. {{Characterization of Autism Spectrum Disorder across the Age Span by Intrinsic Network Patterns}}. {Brain topography}. 2019.
Autism spectrum disorder (ASD) is characterized by abnormal functional organization of brain networks, which may underlie the cognitive and social impairments observed in affected individuals. The present study characterizes unique intrinsic connectivity within- and between- neural networks in children through to adults with ASD, relative to controls. Resting state fMRI data were analyzed in 204 subjects, 102 with ASD and 102 age- and sex-matched controls (ages 7-40 years), acquired on a single scanner. ASD was assessed using the autism diagnostic observation schedule (ADOS). BOLD correlations were calculated between 47 regions of interest, spanning seven resting state brain networks. Partial least squares (PLS) analyses evaluated the association between connectivity patterns and ASD diagnosis as well as ASD severity scores. PLS demonstrated dissociable connectivity patterns in those with ASD, relative to controls. Similar patterns were observed in the whole cohort and in a subgroup analysis of subjects under 18 years of age. Greater inter-network connectivity was seen in ASD with greater intra-network connectivity in controls. In conclusion, stronger inter-network and weaker intra-network resting state-fMRI BOLD correlations characterize ASD and may differentiate control and ASD cohorts. These findings are relevant to understanding ASD as a disruption of network topology.
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7. Patra S, Nebhinani N, Viswanathan A, Kirubakaran R. {{Atomoxetine for attention deficit hyperactivity disorder in children and adolescents with autism: A systematic review and meta-analysis}}. {Autism Res}. 2019.
Atomoxetine is prescribed to children with autism spectrum disorder having symptoms of attention deficit hyperactivity disorder. We sought to examine the efficacy and safety of atomoxetine in this population. After screening for inclusion criteria, we identified three randomized placebo controlled trials involving 241 children. We assessed internal validity using standard Cochrane Risk of bias tool for randomized controlled trials (RCTs). We used Revman 5.3 for meta-analysis and GRADE approach to create summary of findings with grading of the quality of evidence. Atomoxetine had a benefit on improving parent-rated hyperactivity (standardized mean difference [SMD] = -0.73, 95% Confidence Interval, CI = -1.15 to -0.34) and parent-rated inattention (SMD = -0.53, 95% CI = -0.93 to -0.12) but the magnitude of effects is uncertain. However, atomoxetine was also associated with increased risk of non-serious adverse effects like nausea and vomiting, decreased sleep, and decreased appetite. Atomoxetine may be effective in improving hyperactivity and inattention in children with autism spectrum disorder and attention deficit hyperactivity disorder. However, we are uncertain about the true effect of this intervention and need more RCTs trials designed to evaluate this. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Atomoxetine is prescribed for Attention Deficit Hyperactivity Disorder (ADHD). About a third of children and adolescents with autism also suffer from ADHD. We carried out an analysis of data reported from a specific kind of medication trials which had examined the effectiveness and side effects of atomoxetine in this patient population. We could find only three such trials and analyzed the reported data. Our analysis revealed that atomoxetine is effective in improving symptoms of ADHD like hyperactivity and inattention and also causes side effects like nausea, vomiting, decreased sleep, and decreased appetite. However, the existing data are insufficient to provide a conclusive statement with certainty and more trials are needed for this.
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8. Rhine MA, Parrott JM, Schultz MN, Kazdoba TM, Crawley JN. {{Hypothesis-driven investigations of diverse pharmacological targets in two mouse models of autism}}. {Autism Res}. 2019.
Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA-approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well-replicated autism-relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan-McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA-A receptor agonist gaboxadol significantly reduced repetitive self-grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8-DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d-cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions in repetitive behavior by a GABA-A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors by a TrkB receptor agonist, in mouse models of autism.
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9. Wang ZJ, Zhong P, Ma K, Seo JS, Yang F, Hu Z, Zhang F, Lin L, Wang J, Liu T, Matas E, Greengard P, Yan Z. {{Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice}}. {Mol Psychiatry}. 2019.
Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.
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10. Yamamoto-Sasaki M, Yoshida S, Takeuchi M, Tanaka-Mizuno S, Ogawa Y, Furukawa TA, Kawakami K. {{Association between antidepressant use during pregnancy and autism spectrum disorder in children: a retrospective cohort study based on Japanese claims data}}. {Maternal health, neonatology and perinatology}. 2019; 5: 1.
Background: Studies using data from Western countries have raised concerns that treating pregnant women with antidepressants may increase the risk of autism spectrum disorders (ASDs) in their offspring. However, to date, the studies are inconclusive. We therefore examined the association between antidepressant use and ASD using claims data collected in Japan. Methods: This retrospective cohort study was based on claims data from mothers and their children from January 2005 to July 2014, obtained from the Japan Medical Data Center. The information from mothers and children was linked using the family identification code. Information on antidepressant prescriptions during pregnancy was extracted from the database. To collect information on ASD, children for whom data were available 24 months or more after birth were followed up from birth through July 2014 or up until their withdrawal from the database. To ensure appropriate diagnosis of ASD, mother-child pairs where the children’s data did not cover the 24 months after birth or pairs where children had a diagnosis of ASD within only 23 months after birth were excluded from the study cohort. We used logistic regression analyses to evaluate the association between antidepressant use during pregnancy and the children’s ASD diagnosis. All statistical analyses were performed using IBM SPSS (Statistical Package for the Social Sciences) Statistics ver. 21.0. Results: Of the 53,864 eligible mother-child pairs, 26,925 met the study criteria. Crude analysis showed that the ASD prevalence in children was significantly higher with any antidepressant use than with non-use (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.08, 4.95). However, when the analysis was adjusted for the confounding effect of maternal depression during pregnancy, statistical significance was lost (OR, 0.76; CI, 0.27, 2.18). Conclusions: After adjustment for confounders, we found no significant association between antidepressant use during pregnancy and ASD in children in Japan. This result provides additional evidence to support the idea that antidepressant use during pregnancy itself is not associated with an increase in ASD in children. In addition, this represents the first evidence based on Asian data.
