1. Bales KL, Solomon M, Jacob S, Crawley JN, Silverman JL, Larke RH, Sahagun E, Puhger KR, Pride MC, Mendoza SP. {{Long-term exposure to intranasal oxytocin in a mouse autism model}}. {Transl Psychiatry};2014;4:e480.
Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8 IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse’s chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT.
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2. Dinnissen M, Dietrich A, van den Hoofdakker BJ, Hoekstra PJ. {{Clinical and pharmacokinetic evaluation of risperidone for the management of autism spectrum disorder}}. {Expert Opin Drug Metab Toxicol};2014 (Nov 11):1-14.
Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is often accompanied by psychiatric comorbidity. Although there is no medication currently available to treat the core symptoms of ASD, risperidone was the first drug to be approved for use in ASD and is still the best established psychopharmacological option for the treatment of irritability and behavioral problems in ASD. Areas covered: This article gives an overview of the pharmacokinetic profile of risperidone and a comprehensive review of treatment studies regarding the use of risperidone in ASD. Expert opinion: Ample evidence supports the short-term use of risperidone for treating irritability and behavioral problems in ASD. Risperidone also shows promise in treating symptoms often associated with ASD, such as stereotypical behavior, social difficulties, hyperactivity and cognitive problems. However, several adverse effects have been identified; most are mild or moderate and well manageable, but weight gain and metabolic changes are a considerable concern. Therefore, risperidone should in our view be seen as ‘a last resort’, only justified for the short-term treatment of serious behavioral problems, which have failed to respond sufficiently to behavioral interventions. Future studies should investigate long-term effects of risperidone and factors that facilitate individual risk-benefit analyses before treatment.
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3. Fakroon S, Arheiam A, Omar S. {{Dental caries experience and periodontal treatment needs of children with autistic spectrum disorder}}. {Eur Arch Paediatr Dent};2014 (Nov 11)
AIM: To assess dental caries experience and periodontal treatment needs among Libyan children diagnosed with autistic spectrum disorder (ASD). MATERIALS AND METHODS: A cross-sectional, comparative case-control study was used, in which dental caries experience of 50 children with ASD was compared with that of 50 controls. The children with ASD were recruited from Benghazi Centre of Children with ASD, Libya. Controls were recruited from school children and matched for age, gender and socioeconomic status. DMFT, dmft for dental caries experience and CPITN for periodontal treatment needs were calculated according to WHO criteria by a calibrated examiner. Scores for DMFT as well as CPITN indices were compared using bivariate analysis. RESULTS: The data analysed for this study comprised observations from a group of children (cases = 50) diagnosed with ASD matched with healthy children (controls = 50). Consequently, each group consisted of 40 males and 10 females aged between 3 and 14 years (mean 7.29 +/- 3.11). The ASD children showed significantly lower means for DMFT and dmft teeth as well as higher periodontal treatment needs (p > 0.05). CONCLUSION: Children with ASD were found to be more likely caries-free and have lower DMFT scores and higher unmet periodontal treatment needs than did the unaffected control children.
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4. Griesi-Oliveira K, Acab A, Gupta AR, Sunaga DY, Chailangkarn T, Nicol X, Nunez Y, Walker MF, Murdoch JD, Sanders SJ, Fernandez TV, Ji W, Lifton RP, Vadasz E, Dietrich A, Pradhan D, Song H, Ming GL, Gu X, Haddad G, Marchetto MC, Spitzer N, Passos-Bueno MR, State MW, Muotri AR. {{Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons}}. {Mol Psychiatry};2014 (Nov 11)
An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function. The observed neuronal phenotypes could then be rescued by TRPC6 complementation and by treatment with insulin-like growth factor-1 or hyperforin, a TRPC6-specific agonist, suggesting that ASD individuals with alterations in this pathway may benefit from these drugs. We also demonstrate that methyl CpG binding protein-2 (MeCP2) levels affect TRPC6 expression. Mutations in MeCP2 cause Rett syndrome, revealing common pathways among ASDs. Genetic sequencing of TRPC6 in 1041 ASD individuals and 2872 controls revealed significantly more nonsynonymous mutations in the ASD population, and identified loss-of-function mutations with incomplete penetrance in two patients. Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model. This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.Molecular Psychiatry advance online publication, 11 November 2014; doi:10.1038/mp.2014.141.
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5. Harstad EB, Fogler J, Sideridis G, Weas S, Mauras C, Barbaresi WJ. {{Comparing Diagnostic Outcomes of Autism Spectrum Disorder Using DSM-IV-TR and DSM-5 Criteria}}. {J Autism Dev Disord};2014 (Nov 11)
Controversy exists regarding the DSM-5 criteria for ASD. This study tested the psychometric properties of the DSM-5 model and determined how well it performed across different gender, IQ, and DSM-IV-TR sub-type, using clinically collected data on 227 subjects (median age = 3.95 years, majority had IQ > 70). DSM-5 was psychometrically superior to the DSM-IV-TR model (Comparative Fit Index of 0.970 vs 0.879, respectively). Measurement invariance revealed good model fit across gender and IQ. Younger children tended to meet fewer diagnostic criteria. Those with autistic disorder were more likely to meet social communication and repetitive behaviors criteria (p < .001) than those with PDD-NOS. DSM-5 is a robust model but will identify a different, albeit overlapping population of individuals compared to DSM-IV-TR.
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6. Koch L. {{Disease genetics: New insights into the genetic architecture of ASDs}}. {Nat Rev Genet};2014 (Nov 11)
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7. Merrick J, Morad M, Carmeli E. {{Intellectual and developmental disabilities: male health}}. {Front Public Health};2014;2:208.
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8. Pagan C, Delorme R, Callebert J, Goubran-Botros H, Amsellem F, Drouot X, Boudebesse C, Le Dudal K, Ngo-Nguyen N, Laouamri H, Gillberg C, Leboyer M, Bourgeron T, Launay JM. {{The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders}}. {Transl Psychiatry};2014;4:e479.
Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35-46%) of patients), as well as the deficit in melatonin (51% (45-57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41-54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS-melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS-melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.
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9. Seese RR, Wang K, Yao YQ, Lynch G, Gall CM. {{Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice}}. {Proc Natl Acad Sci U S A};2014 (Nov 10)
Recent studies have shown that short, spaced trains of afferent stimulation produce much greater long-term potentiation (LTP) than that obtained with a single, prolonged stimulation episode. The present studies demonstrate that spaced training regimens, based on these LTP timing rules, facilitate learning in wild-type (WT) mice and can offset learning and synaptic signaling impairments in the fragile X mental retardation 1 (Fmr1) knockout (KO) model of fragile X syndrome. We determined that 5 min of continuous training supports object location memory (OLM) in WT but not Fmr1 KO mice. However, the same amount of training distributed across three short trials, spaced by one hour, produced robust long-term memory in the KOs. At least three training trials were needed to realize the benefit of spacing, and intertrial intervals shorter or longer than 60 min were ineffective. Multiple short training trials also rescued novel object recognition in Fmr1 KOs. The spacing effect was surprisingly potent: just 1 min of OLM training, distributed across three trials, supported robust memory in both genotypes. Spacing also rescued training-induced activation of synaptic ERK1/2 in dorsal hippocampus of Fmr1 KO mice. These results show that a spaced training regimen designed to maximize synaptic potentiation facilitates recognition memory in WT mice and can offset synaptic signaling and memory impairments in a model of congenital intellectual disability.
