ABSTRACT
Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Fragile X Syndrome , Animals , Mice , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Fragile X Mental Retardation Protein/genetics , Neurons/metabolism , Phenotype , Mice, Knockout , Disease Models, AnimalABSTRACT
Given significant genetic, molecular, and phenotypic overlaps, researchers have begun to investigate whether targeted treatments for Fragile X Syndrome (FXS) could also be beneficial for patients with Autism Spectrum Disorder (ASD). For example, low-dose sertraline, an SSRI, was used in two recent controlled trials in children with FXS and ASD. The first trial recruited 52 children with FXS, 32 of which were also diagnosed with ASD; the second trial recruited 58 children with non-syndromic ASD. One focus of the present study is to compare the response to sertraline between the FXS-associated ASD and non-syndromic ASD groups. Another focus is to compare baseline ASD-related characteristics between the groups and review these differences within the context of recent literature comparing these populations. Our comparison showed more severe ASD profiles in children with non-syndromic ASD vs. FXS-associated ASD. Regarding response to sertraline, the FXS-ASD group displayed significant improvements in language development, while the non-syndromic group did not show any significant improvements. One possible explanation for this differential response is the distinct anxiety profiles that are seen in these two groups. The heightened anxiety phenotype seen in those with FXS-ASD may have led to a greater relief of anxiety symptoms with sertraline compared to those with non-syndromic ASD; this, in turn, could have led to measurably greater developmental gains. Further research is required to solidify this connection between anxiety relief and developmental gains in these populations.
ABSTRACT
To date, the phenotypic significance of EEG abnormalities in patients with ASD is unclear. In a population affected by ASD we aimed to evaluate: the phenotypic characteristics; the prevalence of EEG abnormalities; the potential correlations between EEG abnormalities and behavioral and cognitive variables. Sixty-nine patients with ASD underwent cognitive or developmental testing, language assessment, and adaptive behavior skills evaluation as well as sleep/wake EEG recording. EEG abnormalities were found in 39.13% of patients. EEG abnormalities correlated with autism severity, hyperactivity, anger outbursts, aggression, negative or destructive behavior, motor stereotypies, intellectual disability, language impairment and self-harm. Our findings confirmed that EEG abnormalities are present in the ASD population and correlate with several associated phenotypic features.
Subject(s)
Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/physiopathology , Electroencephalography/methods , Severity of Illness Index , Adolescent , Aggression/physiology , Aggression/psychology , Autism Spectrum Disorder/psychology , Biomarkers , Child , Child, Preschool , Cohort Studies , Female , Humans , Intellectual Disability/diagnosis , Intellectual Disability/physiopathology , Intellectual Disability/psychology , Male , Pilot Projects , Retrospective Studies , Stereotyped Behavior/physiology , Young AdultABSTRACT
The fragile X syndrome (FXS) is caused by silencing of the fragile X mental retardation gene (FMR1) and the absence of its product, fragile X mental retardation protein (FMRP), resulting from CpG island methylation associated with large CGG repeat expansions (more than 200) termed full mutation (FM). We have identified a number of novel epigenetic markers for FXS using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), naming the most informative fragile X-related epigenetic element 1 (FREE1) and 2 (FREE2). Methylation of both regions was correlated with that of the FMR1 CpG island detected using Southern blot (FREE1 R = 0.97; P < 0.00001, n = 23 and FREE2 R = 0.93; P < 0.00001, n = 23) and negatively correlated with lymphocyte expression of FMRP (FREE1 R = -0.62; P = 0.01, n = 15 and FREE2 R = -0.55; P = 0.03, n = 15) in blood of partially methylated 'high functioning' FM males. In blood of FM carrier females, methylation of both markers was inversely correlated with the FMR1 activation ratio (FREE1 R = -0.93; P < 0.0001, n = 12 and FREE2 R = -0.95; P < 0.0001, n = 9). In a sample set of 49 controls, 18 grey zone (GZ 40-54 repeats), 22 premutation (PM 55-170 repeats) and 22 (affected) FXS subjects, the FREE1 methylation pattern was consistent between blood and chorionic villi as a marker of methylated FM alleles and could be used to differentiate FXS males and females from controls, as well as from carriers of GZ/PM alleles, but not between GZ and PM alleles and controls. Considering its high-throughput and specificity for pathogenic FM alleles, low cost and minimal DNA requirements, FREE MALDI-TOF MS offers a unique tool in FXS diagnostics and newborn population screening.
