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. 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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3. Israelyan N, Margolis KG. {{Reprint of: Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders}}. {Pharmacological research}. 2019.
Autism-spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive patterns of behavior. ASD is, however, often associated with medical comorbidities and gastrointestinal (GI) dysfunction is among the most common. Studies have demonstrated a correlation between GI dysfunction and the degree of social impairment in ASD. The etiology of GI abnormalities in ASD is unclear, though the association between GI dysfunction and ASD-associated behaviors suggest that overlapping developmental defects in the brain and the intestine and/or a defect in communication between the enteric and central nervous systems (ENS and CNS, respectively), known as the gut-brain axis, could be responsible for the observed phenotypes. Brain-gut abnormalities have been increasingly implicated in several disease processes, including ASD. As a critical modulator of ENS and CNS development and function, serotonin may be a nexus for the gut-brain axis in ASD. This paper reviews the role of serotonin in ASD from the perspective of the ENS. A murine model that has been demonstrated to possess brain, behavioral and GI abnormalities mimicking those seen in ASD harbors the most common serotonin transporter (SERT) based mutation (SERT Ala56) found in children with ASD. Discussion of the gut-brain manifestations in the SERT Ala56 mice, and their correction with developmental administration of a 5-HT4 agonist, are also addressed in conjunction with other future directions for diagnosis and treatment.
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4. Mikami AY, Miller M, Lerner MD. {{Social functioning in youth with attention-deficit/hyperactivity disorder and autism spectrum disorder: transdiagnostic commonalities and differences}}. {Clinical psychology review}. 2019.
Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are both neurodevelopmental disorders originating in childhood with high associated impairments and public health significance. There has been growing recognition of the frequent co-occurrence, and potential interrelatedness, between ADHD and ASD without intellectual disability. In fact, the most recent (5th) edition of the DSM is the first to allow ADHD and ASD to be diagnosed in the same individual. The study of transdiagnostic features in ADHD and ASD is important for understanding, and treating, these commonly co-occurring disorders. Social impairment is central to the description and prognosis of both disorders, and many youth with some combination of ADHD and ASD present to clinics for social skills training interventions. However, the aspects of social functioning that are impaired may have both shared and distinct features between the two disorders, relating to some overlapping and some diverse etiologies of social problems in ADHD compared to ASD. These findings have implications for interventions to address social problems in youth with these conditions. We conclude with a discussion about areas for future research and novel intervention targets in youth with ADHD, ASD, and their comorbidity.
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5. 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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6. Nagamoto Y, Okuda S, Matsumoto T, Sugiura T, Takahashi Y, Iwasaki M. {{In Reply to the Letter to the Editor Regarding « Lumbar PLIF and Repeated ASD: An Important Issue with Profound Impact »}}. {World neurosurgery}. 2019.
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7. Uren J, Richdale AL, Cotton SM, Whitehouse AJO. {{Sleep problems and anxiety from 2 to 8 years and the influence of autistic traits: a longitudinal study}}. {Eur Child Adolesc Psychiatry}. 2019.
Whether or not childhood sleep problems and anxiety occur simultaneously, or one precedes the other, and any effect of autistic traits on this relationship remains unclear. We investigated longitudinal associations between sleep and anxiety at 2 years and sleep and anxiety at 8 years controlling for demographic variables. We also examined the additional influence of autistic traits at 2 years on sleep problems and anxiety at 8 years. Participants were from the Western Australian Pregnancy Cohort (Raine) Study, where 2900 pregnant women were recruited between 1989 and 1991 and their children assessed every 2-3 years thereafter. Demographic information was provided at 16-18 weeks gestation. Children’s sleep and anxiety at 2 and 8 years and autistic traits at 2 years were measured using the Child Behavior Checklist. Hierarchical multiple regression models tested the prediction of both anxiety and sleep problems at 8 years. Sleep problems at 2 years and 8 years, anxiety at 2 years, and autistic traits at 2 years were significantly associated with anxiety at 8 years. Sleep problems at 2 years and anxiety at 8 years were significantly related to sleep problems at 8 years. Each of these models explained about 20% of variance. Childhood sleep problems, anxiety and autistic traits are interrelated and can occur concurrently in young children, but the best predictor of poor sleep in middle childhood is concurrent anxiety and vice versa. Anxiety and sleep problems may be an early indicator of autism in young children and early autistic traits may also contribute to anxiety problems later in childhood.
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8. 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.
