1. Brager DH, Johnston D. {{Channelopathies and Dendritic Dysfunction in Fragile X syndrome}}. {Brain Res Bull};2014 (Jan 23)
Dendritic spine abnormalities and the metabotropic glutamate receptor theory put the focus squarely on synapses and protein synthesis as the cellular locus of Fragile X syndrome. Synapses however, are only partly responsible for information processing in neuronal networks. Neurotransmitter triggered excitatory postsynaptic potentials (EPSPs) are shaped and integrated by dendritic voltage-gated ion channels. These EPSPs, and in some cases the resultant dendritic spikes, are further modified by dendritic voltage-gated ion channels as they propagate to the soma. If the resultant somatic depolarization is large enough, action potential(s) will be triggered and propagate both orthodromically down the axon, where it may trigger neurotransmitter release, and antidromically back into the dendritic tree, where it can activate and modify dendritic voltage-gated and receptor activated ion channels. Several channelopathies, both soma-dendritic (L-type calcium channels, Slack potassium channels, h-channels, A-type potassium channels) and axo-somatic (BK channels and delayed rectifier potassium channels) were identified in the fmr1-/y mouse model of Fragile X syndrome. Pathological function of these channels will strongly influence the excitability of individual neurons as well as overall network function. In this chapter we discuss the role of voltage-gated ion channels in neuronal processing and describe how identified channelopathies in models of Fragile X syndrome may play a role in dendritic pathophysiology.
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2. Hall SS, Hustyi KM, Hammond JL, Hirt M, Reiss AL. {{Using Discrete Trial Training to Identify Specific Learning Impairments in Boys with Fragile X Syndrome}}. {J Autism Dev Disord};2014 (Jan 23)
We examined whether discrete trial training (DTT) could be used to identify learning impairments in mathematical reasoning in boys with fragile X syndrome (FXS). Boys with FXS, aged 10-23 years, and age and IQ-matched controls, were trained to match fractions to pie-charts and pie-charts to decimals either on a computer or with a trained behavior analyst using DTT. Participants with FXS obtained significantly lower learning rates on the fractions to pie-charts task, and were more likely to perseverate on previously reinforced responses during learning compared to controls. These data suggest that DTT can be used to identify specific learning impairments in boys with FXS, as well as other low-functioning individuals with developmental disabilities.
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3. Horiuchi F, Oka Y, Uno H, Kawabe K, Okada F, Saito I, Tanigawa T, Ueno SI. {{Age- and gender-related emotional and behavioral problems in children with autism spectrum disorders: comparison with control children}}. {Psychiatry Clin Neurosci};2014 (Jan 22)
AIM: Children with autism spectrum disorders (ASD) often present with emotional and behavioral problems, which could change the clinical course especially during childhood and affect future quality of life. The aim of this study was to clarify the-age- and gender-related differences of these problems in ASD. METHODS: The study subjects were 173 patients with ASD (age: 4-16 years) and 173 age- and gender-matched community children (control group). The parent version of Strengths and Difficulties Questionnaire (SDQ) was used for comparison of the emotional and behavioral problems between the two groups. RESULTS: The SDQ scores were significantly higher in children with ASD than controls at all ages. The score of total difficulties was significantly higher in females with ASD than in their male counterparts, while the score in male controls was significantly higher than in female controls. Age-related differences in emotional and behavioral problems were observed both in children with ASD and controls, but the characteristics were different: in children with ASD, emotional symptoms and peer problems in both genders and conduct problems in females increased significantly with age, while none of the problems in the controls changed with age except for a decrease in the score of hyperactivity/inattention developmentally in both genders. Prosocial behaviors of children with ASD and controls showed small changes with age. CONCLUSION: Emotional and behavioral problems are common in children with ASD and showed age- and gender-related differences. Our study emphasized the importance of recognizing those differences among children with ASD for early intervention.
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4. Keil AP, Daniels JL, Hertz-Picciotto I. {{Autism spectrum disorder, flea and tick medication, and adjustments for exposure misclassification: the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study}}. {Environ Health};2014 (Jan 23);13(1):3.
BACKGROUND: The environmental contribution to autism spectrum disorders (ASD) is largely unknown, but household pesticides are receiving increased attention. We examined associations between ASD and maternally-reported use of imidacloprid, a common flea and tick treatment for pets. METHODS: Bayesian logistic models were used to estimate the association between ASD and imidacloprid and to correct for potential differential exposure misclassification due to recall in a case control study of ASD. RESULTS: Our analytic dataset included complete information for 262 typically developing controls and 407 children with ASD. Compared with exposure among controls, the odds of prenatal imidacloprid exposure among children with ASD were slightly higher, with an odds ratio (OR) of 1.3 (95% Credible Interval [CrI] 0.78, 2.2). A susceptibility window analysis yielded higher ORs for exposures during pregnancy than for early life exposures, whereas limiting to frequent users of imidacloprid, the OR increased to 2.0 (95% CI 1.0, 3.9). CONCLUSIONS: Within plausible estimates of sensitivity and specificity, the association could result from exposure misclassification alone. The association between imidacloprid exposure and ASD warrants further investigation, and this work highlights the need for validation studies regarding prenatal exposures in ASD.
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5. Koldewyn K, Yendiki A, Weigelt S, Gweon H, Julian J, Richardson H, Malloy C, Saxe R, Fischl B, Kanwisher N. {{Differences in the right inferior longitudinal fasciculus but no general disruption of white matter tracts in children with autism spectrum disorder}}. {Proc Natl Acad Sci U S A};2014 (Jan 21)
One of the most widely cited features of the neural phenotype of autism is reduced « integrity » of long-range white matter tracts, a claim based primarily on diffusion imaging studies. However, many prior studies have small sample sizes and/or fail to address differences in data quality between those with autism spectrum disorder (ASD) and typical participants, and there is little consensus on which tracts are affected. To overcome these problems, we scanned a large sample of children with autism (n = 52) and typically developing children (n = 73). Data quality was variable, and worse in the ASD group, with some scans unusable because of head motion artifacts. When we follow standard data analysis practices (i.e., without matching head motion between groups), we replicate the finding of lower fractional anisotropy (FA) in multiple white matter tracts. However, when we carefully match data quality between groups, all these effects disappear except in one tract, the right inferior longitudinal fasciculus (ILF). Additional analyses showed the expected developmental increases in the FA of fiber tracts within ASD and typical groups individually, demonstrating that we had sufficient statistical power to detect known group differences. Our data challenge the widely claimed general disruption of white matter tracts in autism, instead implicating only one tract, the right ILF, in the ASD phenotype.
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6. Ludwig AL, Espinal GM, Pretto D, Jamal AL, Arque G, Tassone F, Berman RF, Hagerman PJ. {{CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size}}. {Hum Mol Genet};2014 (Jan 23)
Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200 CGG repeats; premutation) result in the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by « toxicity » of expanded-CGG repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wildtype and 97 expanded-CGG-repeat mice carrying up to approximately 250 CGG repeats. While Fmr1 message levels increased with repeat length, FMRP levels trended downward over the same range, subject to significant inter-subject variation. Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mild FMRP decrease in mice mirrored the more limited data for FMRP expression in the human samples. In addition, FMRP expression levels varied in a subset of mice across the cerebellum, frontal cortex, and hippocampus, as well as at different ages. These results provide a foundation for understanding both the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.
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7. Merali Z, Presti-Torres J, Mackay JC, Johnstone J, Du L, St-Jean A, Levesque D, Kent P, Schwartsmann G, Roesler R, Schroder N, Anisman H. {{Long-term behavioral effects of neonatal blockade of gastrin-releasing peptide receptors in rats: similarities to Autism Spectrum Disorders}}. {Behav Brain Res};2014 (Jan 23)
Gastrin releasing peptide, the mammalian counterpart of the amphibian peptide, Bombesin, has been increasingly implicated in regulating normal brain function as well as in the pathogenesis of psychiatric and/or neurodevelopmental disorders. We have previously shown that the neonatal blockade of the gastrin-releasing peptide receptor (GRPr) in rats produces long-lasting consequences during central nervous system development that are commonly observed in neurodevelopmental disorders such as autism spectrum disorders. The present investigation assessed in further detail, long-term behavioral effects of neonatal GRPr blockade. During postnatal days 1 to10, male Wistar rat pups (n=5-10/litter) were injected (subcutaneously) with the GRPr antagonist, RC-3095 (1mg/kg), or a vehicle (control), twice daily. Following the drug treatment regimen, several behaviors were assessed (starting on postnatal day 14) including specific social behaviors (namely, group huddling characteristics, social interaction, and social approach), restrictive/repetitive and stereotyped behaviors (y-maze, repetitive novel objection contact task, observation for stereotypies) and anxiety/fear-related responses (open field, elevated plus maze and contextual fear conditioning). Rats treated neonatally with RC-3095 showed reduced sociability, restrictive interests, motor stereotypies and enhanced learned fear response compared to the controls (vehicle-treated rats). These behavioral abnormalities are consistent with those observed in autism spectrum disorders and provide further evidence that neonatal blockade of GRPr could potentially serve as a useful model to gain a better understanding of the underlying neurodevelopmental disruptions contributing to the expression of autism-relevant phenotypes.
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8. Myrick LK, Nakamoto-Kinoshita M, Lindor NM, Kirmani S, Cheng X, Warren ST. {{Fragile X syndrome due to a missense mutation}}. {Eur J Hum Genet};2014 (Jan 22)
Fragile X syndrome is a common inherited form of intellectual disability and autism spectrum disorder. Most patients exhibit a massive CGG-repeat expansion mutation in the FMR1 gene that silences the locus. In over two decades since the discovery of FMR1, only a single missense mutation (p.(Ile304Asn)) has been reported as causing fragile X syndrome. Here we describe a 16-year-old male presenting with fragile X syndrome but without the repeat expansion mutation. Rather, we find a missense mutation, c.797G>A, that replaces glycine 266 with glutamic acid (p.(Gly266Glu)). The Gly266Glu FMR protein abolished many functional properties of the protein. This patient highlights the diagnostic utility of FMR1 sequencing.European Journal of Human Genetics advance online publication, 22 January 2014; doi:10.1038/ejhg.2013.311.
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9. Nicholas DB, Attridge M, Zwaigenbaum L, Clarke M. {{Vocational support approaches in autism spectrum disorder: A synthesis review of the literature}}. {Autism};2014 (Jan 21)
This synthesis-based analysis identifies and reviews studies evaluating vocational resources for adults with autism spectrum disorder. It is based on a larger systematic review of intervention studies in autism spectrum disorder, from which a critical interpretive synthesis was conducted on studies related to vocation and autism spectrum disorder. In total, 10 studies were found that examine employment support for youth and adults with autism spectrum disorder. Two domains of vocational intervention in the literature were found: supported employment including community placement and job coaching and media and technology-based augmentative tools. The literature is limited in volume and quality of methodology, yet emerging constructs are promising in introducing the utility of vocational resources, in particular, supported employment in community settings. These vocational approaches are examined, along with representative studies. Recommendations for advancing practice, community capacity, and research are offered.
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10. Rotholz DA, Moseley CR, Carlson KB. {{State policies and practices in behavior supports for persons with intellectual and developmental disabilities in the United States: a national survey}}. {Intellect Dev Disabil};2013 (Dec);51(6):433-445.
Abstract Providing effective behavioral supports to decrease challenging behavior and replace it with appropriate alternative skills is essential to meeting the needs of many individuals with intellectual and developmental disabilities (IDD). It is also necessary for fulfilling the requirements of Medicaid-funded individual support plans and is important for moral, ethical, and societal reasons. Unfortunately, there is no national standard for behavioral support practices or source of information on the status of behavior support policies, practices, and services for adults with IDD at either state or national levels. The collection of comprehensive data on state behavior support definitions, provider qualifications, training, and oversight requirements is a necessary starting point for the development of plans to address needed policy and practice changes. This survey is the first national assessment of state policies and practices regarding the definition and delivery of behavior support services to people with intellectual and developmental disabilities receiving publicly financed supports in the United States.
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11. Seese RR, Maske AR, Lynch G, Gall CM. {{Long-Term Memory Deficits are Associated with Elevated Synaptic ERK1/2 Activation and Reversed by mGluR5 Antagonism in an Animal Model of Autism}}. {Neuropsychopharmacology};2014 (Jan 22)
A significant proportion of patients with autism exhibit some degree of intellectual disability. The BTBR T+ Itpr3tf/J mouse strain exhibits behaviors that align with the major diagnostic criteria of autism. To further evaluate the BTBR strain’s cognitive impairments, we quantified hippocampus-dependent object location memory (OLM) and found that one-third of the BTBR mice exhibited robust memory while the remainder did not. Fluorescence deconvolution tomography was used to test if synaptic levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that contributes importantly to plasticity, correlate with OLM scores in individual mice. In hippocampal field CA1, the BTBRs had fewer post-synaptic densities associated with high levels of phosphorylated (p-) ERK1/2 as compared to C57BL/6 mice. Although counts of p-ERK1/2 immunoreactive synapses did not correlate with OLM performance, the intensity of synaptic p-ERK1/2 immunolabeling was negatively correlated with OLM scores across BTBRs. Metabotropic glutamate receptor (mGluR) 5 signaling activates ERK1/2. Therefore, we tested if treatment with the mGluR5 antagonist MPEP normalizes synaptic and learning measures in BTBR mice: MPEP facilitated OLM and decreased synaptic p-ERK1/2 immunolabeling intensity without affecting numbers of p-ERK1/2+ synapses. In contrast, semi-chronic ampakine treatment, which facilitates memory in other models of cognitive impairment, had no effect on OLM in BTBRs. These results suggest that intellectual disabilities associated with different neurodevelopmental disorders on the autism spectrum require distinct therapeutic strategies based on underlying synaptic pathology.Neuropsychopharmacology accepted article preview online, 22 January 2014. doi:10.1038/npp.2014.13.
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12. Tosh D, Rao KL, Rani HS, Deenadayal DA, Murty US, Grover P. {{Association between fragile X premutation and premature ovarian failure: a case-control study and meta-analysis}}. {Arch Gynecol Obstet};2014 (Jan 23)
AIM: The aim of the present study was to investigate the association between FMR1 premutation and premature ovarian failure (POF) patients in Indian population, and a meta-analysis of published results was undertaken to clarify whether FMR1 premutation consistently contributed to the susceptibility. METHODS: A total of 289 POF samples and 360 control samples were included in the study. Repeat variation was checked using GeneScan technique. Results were analyzed with GeneMapper software. Meta-analysis was performed using the Open Meta-Analyst and STATA 12.0 software. The crude odds ratio with 95 % confidence interval (CI) was computed to assess the strength of the associations. RESULTS: The assayed case and control population showed 29 different CGG repeat sizes (alleles), ranging from 7 to 40. Within this population, we found that the CGG repeat length polymorphisms were within the normal range of 6-55 in both patients as well as control samples. Eleven case-control studies were included in the meta-analysis with a total of 1,313 POF cases and 3,132 control subjects. Our meta-analysis revealed that there was a significant difference in the incidence of FMR1 premutation between POF cases and control subjects with p value <0.001 (OR 5.41; 95 % CI 2.53, 11.61). CONCLUSIONS: We found no significant association between FMR1 CGG repeat premutation and POF in Indian population. However, the meta-analysis showed an increased risk of POF associated with a premutation, especially among populations from European descent. Further functional research should be performed to explain the inconsistent results in different ethnicities and POF susceptibility.
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13. von Leden RE, Curley LC, Greenberg GD, Hunsaker MR, Willemsen R, Berman RF. {{Reduced Activity-Dependent Protein Levels in a Mouse Model of the Fragile X Premutation}}. {Neurobiol Learn Mem};2014 (Jan 23)
Environmental enrichment results in increased levels of Fmrp in brain and increased dendritic complexity. The present experiment evaluated activity-dependent increases in Fmrp levels in the motor cortex in response to training on a skilled forelimb reaching task in the CGG KI mouse model of the fragile X premutation. Fmrp, Arc, and c-Fos protein levels were quantified by Western blot in the contralateral motor cortex of mice following training to reach for sucrose pellets with a non-preferred paw and compared to levels in the ipsilateral motor cortex. After training, all mice showed increases in Fmrp, Arc, and c-Fos protein levels in the contralateral compared to the ipsilateral hemisphere; however, the increase in CGG KI mice was less than wildtype mice. Increases in Fmrp and Arc proteins scaled with learning, whereas this relationship was not observed with the c-Fos levels. These data suggest the possibility that reduced levels of activity-dependent proteins associated with synaptic plasticity such as Fmrp and Arc may contribute to the neurocognitive phenotype reported in the CGG KI mice and the fragile X premutation.
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14. Wei X, Christiano ER, Yu JW, Wagner M, Spiker D. {{Reading and math achievement profiles and longitudinal growth trajectories of children with an autism spectrum disorder}}. {Autism};2014 (Jan 21)
This study examined the reading and math achievement profiles and longitudinal growth trajectories of a nationally representative sample of children ages 6 through 9 with an autism spectrum disorder. Four distinct achievement profiles were identified: higher-achieving (39%), hyperlexia (9%), hypercalculia (20%) and lower-achieving (32%). Children with hypercalculia and lower-achieving profiles were more likely to be from low socioeconomic families and had lower functional cognitive skills than the higher-achieving profile. All four profiles lost ground in passage comprehension over time. Slower improvement occurred for the higher-achieving group on letter-word identification, the hyperlexia group on conversation abilities and the hypercalculia group on calculation and functional cognitive skills relative to the lower-achieving group.
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15. Williams EC, Zhong X, Mohamed A, Li R, Liu Y, Dong Q, Ananiev GE, Mok JC, Lin BR, Liu J, Chiao C, Cherney R, Li H, Zhang SC, Chang Q. {{Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons}}. {Hum Mol Genet};2014 (Jan 23)
The disease mechanism of Rett syndrome (RTT) is not well understood. Studies in RTT mouse models have suggested a non-cell-autonomous role for astrocytes in RTT pathogenesis. However, it is not clear whether this is also true for human RTT astrocytes. To establish an in vitro human RTT model, we previously generated isogenic induced pluripotent stem cell (iPSC) lines from several RTT patients carrying different disease-causing mutations. Here, we show that these RTT iPSC lines can be efficiently differentiated into astroglial progenitors and glial fibrillary acidic protein-expressing (GFAP+) astrocytes that maintain isogenic status, that mutant RTT astrocytes carrying three different RTT mutations and their conditioned media have adverse effects on the morphology and function of wild-type neurons and that the glial effect on neuronal morphology is independent of the intrinsic neuronal deficit in mutant neurons. Moreover, we show that both insulin-like growth factor 1 (IGF-1) and GPE (a peptide containing the first 3 amino acids of IGF-1) are able to partially rescue the neuronal deficits caused by mutant RTT astrocytes. Our findings confirm the critical glial contribution to RTT pathology, reveal potential cellular targets of IGF-1 therapy and further validate patient-specific iPSCs and their derivatives as valuable tools to study RTT disease mechanism.
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16. Zhubi A, Chen Y, Dong E, Cook EH, Guidotti A, Grayson DR. {{Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum}}. {Transl Psychiatry};2014;4:e349.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by symptoms related to altered social interactions/communication and restricted and repetitive behaviors. In addition to genetic risk, epigenetic mechanisms (which include DNA methylation/demethylation) are thought to be important in the etiopathogenesis of ASD. We studied epigenetic mechanisms underlying the transcriptional regulation of candidate genes in cerebella of ASD patients, including the binding of MeCP2 (methyl CpG binding protein-2) to the glutamic acid decarboxylase 67 (GAD1), glutamic acid decarboxylase 65 (GAD2), and Reelin (RELN) promoters and gene bodies. Moreover, we performed methyl DNA immunoprecipitation (MeDIP) and hydroxymethyl DNA immunoprecipitation (hMeDIP) to measure total 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the same regions of these genes. The enrichment of 5-hmC and decrease in 5-mC at the GAD1 or RELN promoters detected by 5-hmC and 5-mC antibodies was confirmed by Tet-assisted bisulfite (TAB) pyrosequencing. The results showed a marked and significant increase in MeCP2 binding to the promoter regions of GAD1 and RELN, but not to the corresponding gene body regions in cerebellar cortex of ASD patients. Moreover, we detected a significant increase in TET1 expression and an enrichment in the level of 5-hmC, but not 5-mC, at the promoters of GAD1 and RELN in ASD when compared with CON. Moreover, there was increased TET1 binding to these promoter regions. These data are consistent with the hypothesis that an increase of 5-hmC (relative to 5-mC) at specific gene domains enhances the binding of MeCP2 to 5-hmC and reduces expression of the corresponding target genes in ASD cerebella.
