1. Berry-Kravis E, Hagerman R, Visootsak J, Budimirovic D, Kaufmann WE, Cherubini M, Zarevics P, Walton-Bowen K, Wang P, Bear MF, Carpenter RL. {{Arbaclofen in fragile X syndrome: results of phase 3 trials}}. {J Neurodev Disord}. 2017; 9: 3.
BACKGROUND: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. METHODS: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. RESULTS: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). CONCLUSIONS: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS. Lien vers le texte intégral (Open Access ou abonnement)
2. Birmingham E, Smith Johnston KH, Iarocci G. {{Spontaneous Gaze Selection and Following During Naturalistic Social Interactions in School-Aged Children and Adolescents With Autism Spectrum Disorder}}. {Can J Exp Psychol}. 2017.
Using a novel naturalistic paradigm allowing participants the freedom to spontaneously select and follow gaze cues in their environment, this study extends previous research conducted with younger children to determine whether school-age children with autism spectrum disorder (ASD, n = 17) demonstrate abnormal gaze following relative to typically developing (TD, n = 15) children. The participant and experimenter played a series of games, during which the experimenter pseudorandomly averted her gaze toward a social target (person) or a nonsocial target (object). A significant finding was that, relative to TD children, children with ASD were slower to follow the experimenter’s gaze relative to the start of the trial (social targets d = -.93 [-1.70, -.16], nonsocial targets d = -1.05 [-1.88, -.20]). When we analyzed the duration of glances to the experimenter, we found that the ASD group made longer glances relative to TD children, but only in the nonsocial target condition (social targets d = .01 [-.68, .71], nonsocial targets d = -.81 [-1.53, -.08]). Other analyses revealed patterns of gaze selection and following that may help interpret the main findings. Despite the differences in the timing of gaze selection and following, the most common type of responder in both groups was one who followed the experimenter’s gaze on over half of the trials. This pattern of results argues against a clear deficit in social attention in school-age children with ASD and underscores the importance of measuring both the timing of distinct mechanisms of social attention and the context in which these behaviors occur. (PsycINFO Database Record
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3. Budimirovic DB, Berry-Kravis E, Erickson CA, Hall SS, Hessl D, Reiss AL, King MK, Abbeduto L, Kaufmann WE. {{Updated report on tools to measure outcomes of clinical trials in fragile X syndrome}}. {J Neurodev Disord}. 2017; 9: 14.
OBJECTIVE: Fragile X syndrome (FXS) has been the neurodevelopmental disorder with the most active translation of preclinical breakthroughs into clinical trials. This process has led to a critical assessment of outcome measures, which resulted in a comprehensive review published in 2013. Nevertheless, the disappointing outcome of several recent phase III drug trials in FXS, and parallel efforts at evaluating behavioral endpoints for trials in autism spectrum disorder (ASD), has emphasized the need for re-assessing outcome measures and revising recommendations for FXS. METHODS: After performing an extensive database search (PubMed, Food and Drug Administration (FDA)/National Institutes of Health (NIH)’s www.ClinicalTrials.gov, etc.) to determine progress since 2013, members of the Working Groups who published the 2013 Report evaluated the available outcome measures for FXS and related neurodevelopmental disorders using the COSMIN grading system of levels of evidence. The latter has also been applied to a British survey of endpoints for ASD. In addition, we also generated an informal classification of outcome measures for use in FXS intervention studies as instruments appropriate to detect shorter- or longer-term changes. RESULTS: To date, a total of 22 double-blind controlled clinical trials in FXS have been identified through www.ClinicalTrials.gov and an extensive literature search. The vast majority of these FDA/NIH-registered clinical trials has been completed between 2008 and 2015 and has targeted the core excitatory/inhibitory imbalance present in FXS and other neurodevelopmental disorders. Limited data exist on reliability and validity for most tools used to measure cognitive, behavioral, and other problems in FXS in these trials and other studies. Overall, evidence for most tools supports a moderate tool quality grading. Data on sensitivity to treatment, currently under evaluation, could improve ratings for some cognitive and behavioral tools. Some progress has also been made at identifying promising biomarkers, mainly on blood-based and neurophysiological measures. CONCLUSION: Despite the tangible progress in implementing clinical trials in FXS, the increasing data on measurement properties of endpoints, and the ongoing process of new tool development, the vast majority of outcome measures are at the moderate quality level with limited information on reliability, validity, and sensitivity to treatment. This situation is not unique to FXS, since reviews of endpoints for ASD have arrived at similar conclusions. These findings, in conjunction with the predominance of parent-based measures particularly in the behavioral domain, indicate that endpoint development in FXS needs to continue with an emphasis on more objective measures (observational, direct testing, biomarkers) that reflect meaningful improvements in quality of life. A major continuous challenge is the development of measurement tools concurrently with testing drug safety and efficacy in clinical trials.
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4. Erickson CA, Davenport MH, Schaefer TL, Wink LK, Pedapati EV, Sweeney JA, Fitzpatrick SE, Brown WT, Budimirovic D, Hagerman RJ, Hessl D, Kaufmann WE, Berry-Kravis E. {{Fragile X targeted pharmacotherapy: lessons learned and future directions}}. {J Neurodev Disord}. 2017; 9: 7.
Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.
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5. He CX, Cantu DA, Mantri SS, Zeiger WA, Goel A, Portera-Cailliau C. {{Tactile defensiveness and impaired adaptation of neuronal activity in the Fmr1 knockout mouse model of autism}}. {J Neurosci}. 2017.
Sensory hypersensitivity is a common symptom in autism spectrum disorders (ASDs), including Fragile X Syndrome (FXS), and frequently leads to tactile defensiveness. In mouse models of ASDs, there is mounting evidence of neuronal and circuit hyperexcitability in several brain regions, which could contribute to sensory hypersensitivity. However, it is not yet known whether or how sensory stimulation might trigger abnormal sensory processing at the circuit level or abnormal behavioral responses in ASD mouse models, especially during an early developmental time when experience-dependent plasticity shapes such circuits. Using a novel assay, we discovered exaggerated motor responses to whisker stimulation in young Fmr1 knockout (KO) mice (postnatal days (P) 14-16), a model of FXS. Adult Fmr1 KO mice actively avoided a stimulus that was innocuous to wild-type controls, a sign of tactile defensiveness. Using in vivo two-photon calcium imaging of Layer 2/3 barrel cortex neurons expressing GCaMP6s, we found no differences between wild-type and Fmr1 KO mice in overall whisker-evoked activity, though 45% fewer neurons in young Fmr1 KO mice responded in a time-locked manner. Notably, we identified a pronounced deficit in neuronal adaptation to repetitive whisker stimulation in both young and adult Fmr1 KO mice. Thus, impaired adaptation in cortical sensory circuits is a potential cause of tactile defensiveness in autism.SIGNIFICANCE STATEMENTWe use a novel paradigm of repetitive whisker stimulation and in vivo calcium imaging to assess tactile defensiveness and barrel cortex activity in young and adult Fmr1 knockout mice, the mouse model of Fragile X Syndrome. We describe evidence of tactile defensiveness, as well as a lack of L2/3 neuronal adaptation in barrel cortex, during whisker stimulation. We propose that a defect in sensory adaptation within local neuronal networks, beginning at a young age and continuing into adulthood, likely contributes to sensory overreactivity in FXS and perhaps other ASDs.
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6. Kaluzna-Czaplinska J, Jozwik-Pruska J, Chirumbolo S, Bjorklund G. {{Tryptophan status in autism spectrum disorder and the influence of supplementation on its level}}. {Metab Brain Dis}. 2017.
Recent reports show that the worldwide incidence of autism spectrum disorder (ASD) is dramatically increasing, although ASD etiology and pathogenesis are still far to be fully elucidated. Some dietary-derived essential compounds, such as the amino acid tryptophan, appear to be impaired in patients with ASD. Tryptophan (Trp) plays a significant role in the human organism and serves as a precursor for a wide range of bioactive compounds, including major neurotransmitters. Research indicates that tryptophan might be deficient in subjects with ASD. Deficiency in the tryptophan level can be retrieved by investigating Trp levels or its major metabolite kynurenine in urines. The purpose of the present study is to quantify tryptophan content in urine samples (n = 236) of ASD patients, who underwent a supplemented dietary panel with B vitamins and magnesium, compared to controls (without this diet regimen). The samples were analyzed with gas chromatography-mass spectrometry. Additionally, the correlation between body mass index (BMI) and the level of this amino acid in urine was accomplished. Basic parameters of urine samples were also evaluated. Statistical evaluations in the concentration of tryptophan in ASD patients with different severity of symptoms were reported. A significant difference in tryptophan levels in all groups was observed. Supplementation with B vitamins and magnesium has an influence on the Trp concentration. Furthermore, no correlation between BMI and tryptophan levels was found. These results assess that the Trp level in ASD subjects is critical and that intake of B vitamins and magnesium with diet might influence its metabolic homeostasis.
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7. Kana RK, Sartin EB, Stevens C, Jr., Deshpande HD, Klein C, Klinger MR, Klinger LG. {{Neural Networks Underlying Language and Social Cognition during Self-Other Processing in Autism Spectrum Disorders}}. {Neuropsychologia}. 2017.
The social communication impairments defining autism spectrum disorders (ASD) may be built upon core deficits in perspective-taking, language processing, and self-other representation. Self-referential processing entails the ability to incorporate self-awareness, self-judgment, and self-memory in information processing. Very few studies have examined the neural bases of integrating self-other representation and semantic processing in individuals with ASD. The main objective of this functional MRI study is to examine the role of language and social brain networks in self-other processing in young adults with ASD. Nineteen high-functioning male adults with ASD and 19 age-sex-and-IQ-matched typically developing (TD) control participants made « yes » or « no » judgments of whether an adjective, presented visually, described them (self) or their favorite teacher (other). Both ASD and TD participants showed significantly increased activity in the medial prefrontal cortex (MPFC) during self and other processing relative to letter search. Analyses of group differences revealed significantly reduced activity in left inferior frontal gyrus (LIFG), and left inferior parietal lobule (LIPL) in ASD participants, relative to TD controls. ASD participants also showed significantly weaker functional connectivity of the anterior cingulate cortex (ACC) with several brain areas while processing self-related words. The LIFG and IPL are important regions functionally at the intersection of language and social roles; reduced recruitment of these regions in ASD participants may suggest poor level of semantic and social processing. In addition, poor connectivity of the ACC may suggest the difficulty in meeting the linguistic and social demands of this task in ASD. Overall, this study provides new evidence of the altered recruitment of the neural networks underlying language and social cognition in ASD.
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8. Keogh K. {{Children with autism need better hospital care, says RCN}}. {Nurs Child Young People}. 2017; 29(5): 6.
Nurses have called for improvements to the care of children with autism in hospitals and the community. About 1% of children in the UK have autism spectrum disorder (ASD), which affects social interaction, behaviour and communication. However, as healthcare services are pushed to breaking point, support for such children is dwindling, the RCN warns.
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9. Li T, Wang X, Pan J, Feng S, Gong M, Wu Y, Li G, Li S, Yi L. {{Reward learning modulates the attentional processing of faces in children with and without autism spectrum disorder}}. {Autism Res}. 2017.
The processing of social stimuli, such as human faces, is impaired in individuals with autism spectrum disorder (ASD), which could be accounted for by their lack of social motivation. The current study examined how the attentional processing of faces in children with ASD could be modulated by the learning of face-reward associations. Sixteen high-functioning children with ASD and 20 age- and ability-matched typically developing peers participated in the experiments. All children started with a reward learning task, in which the children were presented with three female faces that were attributed with positive, negative, and neutral values, and were required to remember the faces and their associated values. After this, they were tested on the recognition of the learned faces and a visual search task in which the learned faces served as the distractor. We found a modulatory effect of the face-reward associations on the visual search but not the recognition performance in both groups despite the lower efficacy among children with ASD in learning the face-reward associations. Specifically, both groups responded faster when one of the distractor faces was associated with positive or negative values than when the distractor face was neutral, suggesting an efficient attentional processing of these reward-associated faces. Our findings provide direct evidence for the perceptual-level modulatory effect of reward learning on the attentional processing of faces in individuals with ASD. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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10. McDonald NM, Murphy HG, Messinger DS. {{Empathic responding in preschool-aged children with familial risk for autism}}. {Autism Res}. 2017.
Individuals with autism spectrum disorder (ASD) show deficits in social and emotional reciprocity, which often include empathic responding. The younger siblings of children with ASD (high-risk siblings) are at elevated risk for ASD and for subclinical deficits in social-emotional functioning. Higher levels of empathy in high-risk siblings during the second and third years of life predict fewer ASD symptoms and likelihood of diagnosis. We conducted a multi-method investigation of empathic responding to an examiner’s accident in 30 low-risk and 48 high-risk siblings with (n = 12) and without ASD outcomes (n = 36) at 4-6 years of age. Empathic responding was measured through behavioral observation and parent report. Prosocial behavior did not differ by ASD outcome. Children with ASD exhibited lower levels of personal distress than high-risk and low-risk siblings without ASD. Per parent report, high-risk siblings without ASD demonstrated higher levels of empathic responding than low-risk children, while the ASD group did not differ from children without ASD on this measure. Higher levels of observed empathic concern, but not prosocial behavior, were associated with lower Social Affect scores on the Autism Diagnostic Observation Schedule in high-risk children. Results suggest that ASD diagnosis and symptoms are associated with reduced emotional responsiveness to an adult’s distress, but not associated with deficits in prosocial behavior at preschool age. Results do not support the idea that empathic responding is negatively impacted in a broader autism phenotype. Findings extend previous research by suggesting that empathy may be a protective factor in the social-emotional development of children with familial risk for ASD. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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11. Morimura N, Yasuda H, Yamaguchi K, Katayama KI, Hatayama M, Tomioka NH, Odagawa M, Kamiya A, Iwayama Y, Maekawa M, Nakamura K, Matsuzaki H, Tsujii M, Yamada K, Yoshikawa T, Aruga J. {{Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice}}. {Nat Commun}. 2017; 8: 15800.
Lrfn2/SALM1 is a PSD-95-interacting synapse adhesion molecule, and human LRFN2 is associated with learning disabilities. However its role in higher brain function and underlying mechanisms remain unknown. Here, we show that Lrfn2 knockout mice exhibit autism-like behavioural abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits, together with enhanced learning and memory. In the hippocampus, the levels of synaptic PSD-95 and GluA1 are decreased. The synapses are structurally and functionally immature with spindle shaped spines, smaller postsynaptic densities, reduced AMPA/NMDA ratio, and enhanced LTP. In vitro experiments reveal that synaptic surface expression of AMPAR depends on the direct interaction between Lrfn2 and PSD-95. Furthermore, we detect functionally defective LRFN2 missense mutations in autism and schizophrenia patients. Together, these findings indicate that Lrfn2/LRFN2 serve as core components of excitatory synapse maturation and maintenance, and their dysfunction causes immature/silent synapses with pathophysiological state.
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12. Ropar D, Greenfield K, Smith AD, Carey M, Newport R. {{Body representation difficulties in children and adolescents with autism may be due to delayed development of visuo-tactile temporal binding}}. {Dev Cogn Neurosci}. 2017.
Recent research suggests visuo-tactile binding is temporally extended in autism spectrum disorders (ASD), although it is not clear whether this specifically underlies altered body representation in this population. In the current study children and adolescents with ASD, and typically developing controls, placed their hand into mediated reality system (MIRAGE) and saw two identical live video images of their own right hand. One image was in the proprioceptively correct location (veridical hand) and the other was displaced to either side. While visuo-tactile feedback was applied via brushstroke to the participant’s (unseen) right finger, they viewed one hand image receiving synchronous brushstrokes and the other receiving brushstrokes with a temporal delay (60, 180 and 300ms). After brushing, both images disappeared from view and participants pointed to a target, with direction of movement indicating which hand was embodied. ASD participants, like younger mental aged-matched controls, showed reduced embodiment of the spatially incongruent, but temporally congruent, hand compared to chronologically age-matched controls at shorter temporal delays. This suggests development of visuo-tactile integration may be delayed in ASD. Findings are discussed in relation to atypical body representation in ASD and how this may contribute to social and sensory difficulties within this population.
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13. Ruta L, Fama FI, Bernava GM, Leonardi E, Tartarisco G, Falzone A, Pioggia G, Chakrabarti B. {{Reduced preference for social rewards in a novel tablet based task in young children with Autism Spectrum Disorders}}. {Sci Rep}. 2017; 7(1): 3329.
Atypical responsivity to social rewards has been observed in young children with or at risk of Autism Spectrum Disorders (ASD). These observations contributed to the hypothesis of reduced social motivation in ASD. In the current study we develop a novel task to test social reward preference using a tablet computer (iPad), where two differently coloured buttons were associated with a social and a nonsocial rewarding image respectively. 63 young children, aged 14-68 months, with and without a diagnosis of ASD took part in the study. The experimental sessions were also recorded on video, using an in-built webcam on the tablet as well as an external camera. Children with ASD were found to show a reduced relative preference for social rewards, indexed by a lower proportion of touches for the button associated with the social reward image. Greater social preference as measured using the tablet-based task was associated with increased use of social communicative behaviour such as eye contact with the experimenter and social smile in response to the social reward image. These results are consistent with earlier findings from eye-tracking studies, and provide novel empirical insights into atypical social reward responsivity in ASD.
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14. Sayad A, Noroozi R, Omrani MD, Taheri M, Ghafouri-Fard S. {{Retinoic acid-related orphan receptor alpha (RORA) variants are associated with autism spectrum disorder}}. {Metab Brain Dis}. 2017.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with various epidemiologic, genetic, epigenetic, and environmental factors being associated with it. The observed sex bias in ASD towards male has prompted investigators to propose sex-dependent mechanisms for ASD. Retinoic acid-related orphan receptor-alpha (RORA) is a new autism candidate gene that has been shown to be differentially regulated by male and female hormones. Previous studies have shown deregulation of its expression in the prefrontal cortex and the cerebellum of ASD patients. In the present study we aimed at identification of the possible associations between two functional polymorphisms in the RORA gene (rs11639084 and rs4774388) and the risk of ASD in 518 Iranian ASD patients and 472 age, gender, and ethnic-matched healthy controls by means of tetra primer-amplification refractory mutation system-PCR. The allele and genotype frequencies of rs11639084 were not significantly different between patients and controls. However, the allele frequencies of rs4774388 showed significant overrepresentation of T allele in patients compared with controls (P = 0.04, OR (95% CI) =1.21 (1.01-1.46)). The rs4774388-TT genotype was significantly higher in patients compared with controls and was associated with ASD risk in dominant inheritance model (P = 0.04, OR (95% CI) =0.77 (0.59-0.99)). Haplotype analysis showed significant association of two estimated blocks of rs11639084/ rs4774388 with ASD risk. Consequently, the present data provide further evidence for RORA participation in the pathogenesis of ASD.
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15. Schaefer TL, Davenport MH, Grainger LM, Robinson CK, Earnheart AT, Stegman MS, Lang AL, Ashworth AA, Molinaro G, Huber KM, Erickson CA. {{Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety}}. {J Neurodev Disord}. 2017; 9: 6.
BACKGROUND: Fragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene (FMR1) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of acamprosate and the significance of the molecule’s calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of acamprosate were assessed in the Fmr1-/y (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments. METHODS: Fmr1 KO mice and their wild-type (WT) littermates were utilized to assess acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic acamprosate treatment and any potential effects of the calcium moiety using CaCl2 treatment on behavior and nuclear ERK1/2 activation. RESULTS: Acamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation. CONCLUSIONS: These data indicate that acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of acamprosate in these instances.
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16. Veenstra-VanderWeele J. {{Translation in fragile X: no home runs in the first at-bat}}. {J Neurodev Disord}. 2017; 9: 21.
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17. Yang S, Guo X, Dong X, Han Y, Gao L, Su Y, Dai W, Zhang X. {{GABAA receptor subunit gene polymorphisms predict symptom-based and developmental deficits in Chinese Han children and adolescents with autistic spectrum disorders}}. {Sci Rep}. 2017; 7(1): 3290.
GABAA receptor subunit genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11-q13 have been implicated in the etiology of autistic spectrum disorders (ASD). This study intended to investigate the possible role of single-nucleotide polymorphisms (SNPs) present in GABRB3 (rs2081648 and rs1426217), GABRA5 (rs35586628), and GABRG3 (rs208129) genes in ASD susceptibility and symptom-based and developmental phenotypes of ASD in Chinese Han children and adolescents. 99 ASD patients and 231 age- and gender- frequency-matched typical developing (TD) controls were tested by TaqMan(R) genotyping assay. Symptom-based phenotypes were evaluated by Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC), and developmental phenotypes were assessed by Early Childhood Development Questionnaire (ECDQ) in ASD patients. Three haplotypes and global chi 2 test of all SNPs demonstrated significant associations between ASD and TD groups. Besides, GABRB3 rs2081648, GABRA5 rs35586628, and GABRG3 rs208129 polymorphisms were associated with symptom-based deficits in social interaction, sensorimotor and somatosensory coordination, visual response, imitation, activity level, language expression and adaptability. Developmental abnormalities in late emergences of social interaction and fine motor were detected in GABRB3 rs2081648 polymorphism. Overall results indicated that gene synergy may participate in ASD pathogenesis, and GABAA receptor gene polymorphisms can predict symptom-based and developmental deficits in ASD individuals.
