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Population structure confounds autism genetic classifier.

November 18, 2014 - 8:22am
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Population structure confounds autism genetic classifier.

Mol Psychiatry. 2014 Apr;19(4):405-7

Authors: Belgard TG, Jankovic I, Lowe JK, Geschwind DH

PMID: 23546168 [PubMed - indexed for MEDLINE]

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis.

November 18, 2014 - 8:22am
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Predicting the diagnosis of autism spectrum disorder using gene pathway analysis.

Mol Psychiatry. 2014 Apr;19(4):504-10

Authors: Skafidas E, Testa R, Zantomio D, Chana G, Everall IP, Pantelis C

Abstract
Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test. This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN). Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective. Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets. In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.

PMID: 22965006 [PubMed - indexed for MEDLINE]

Brief report: regression timing and associated features in MECP2 duplication syndrome.

November 17, 2014 - 8:01am
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Brief report: regression timing and associated features in MECP2 duplication syndrome.

J Autism Dev Disord. 2013 Oct;43(10):2484-90

Authors: Peters SU, Hundley RJ, Wilson AK, Carvalho CM, Lupski JR, Ramocki MB

Abstract
The aim of this study was to determine the frequency, timing, and associated features of developmental regression in MECP2 duplication syndrome. We also examined whether duplication size was associated with regression. Comprehensive psychological evaluations were used to assess 17 boys with MECP2 duplication syndrome. Information about regression was gathered via parent report. Eight of 17 boys exhibited regression in language skills, while seven of 17 exhibited regression in other skill areas. Regression in "other skill" areas coincided with seizure onset and with a prior autism diagnosis in six of seven participants. Regression was not associated with duplication size. Questions remain as to why some boys regress, and future work is necessary to understand the underlying mechanism(s) that causes regression.

PMID: 23456562 [PubMed - indexed for MEDLINE]

Emergence of Autism Spectrum Disorder in Children from Simplex Families: Relations to Parental Perceptions of Etiology.

November 16, 2014 - 7:16am

Emergence of Autism Spectrum Disorder in Children from Simplex Families: Relations to Parental Perceptions of Etiology.

J Autism Dev Disord. 2014 Nov 15;

Authors: Goin-Kochel RP, Mire SS, Dempsey AG

Abstract
Current research describes a four-category scheme of Autism Spectrum Disorder (ASD) onset: early, regressive, plateau, delay + regression. To replicate prevalence of different onset types, ASD onset (per the Autism Diagnostic Interview-Revised) was examined in a large North American sample; for a subset, parents' causal beliefs were ascertained via the Revised Illness Perception Questionnaire to examine potential associations with ASD-onset types. Onset rates were similar across samples, with a slightly higher proportion of children in the subsample categorized with regression. Top-rated causes of ASD were genetics, brain structure, will of God, toxins in vaccines, and environmental pollution. Parents reporting regression more often believed that toxins in vaccines caused ASD. Influences on treatment selection and broader public-health ramifications are discussed.

PMID: 25398603 [PubMed - as supplied by publisher]

A duplication of the whole KIAA2022 gene validates the gene role in the pathogenesis of intellectual disability and autism.

November 15, 2014 - 6:52am

A duplication of the whole KIAA2022 gene validates the gene role in the pathogenesis of intellectual disability and autism.

Clin Genet. 2014 Nov 13;

Authors: Charzewska A, Rzońca S, Janeczko M, Nawara M, Smyk M, Bal J, Hoffman-Zacharska D

PMID: 25394356 [PubMed - as supplied by publisher]

Genomics in neurological disorders.

November 14, 2014 - 6:37am
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Genomics in neurological disorders.

Genomics Proteomics Bioinformatics. 2014 Aug;12(4):156-63

Authors: Han G, Sun J, Wang J, Bai Z, Song F, Lei H

Abstract
Neurological disorders comprise a variety of complex diseases in the central nervous system, which can be roughly classified as neurodegenerative diseases and psychiatric disorders. The basic and translational research of neurological disorders has been hindered by the difficulty in accessing the pathological center (i.e., the brain) in live patients. The rapid advancement of sequencing and array technologies has made it possible to investigate the disease mechanism and biomarkers from a systems perspective. In this review, recent progresses in the discovery of novel risk genes, treatment targets and peripheral biomarkers employing genomic technologies will be discussed. Our major focus will be on two of the most heavily investigated neurological disorders, namely Alzheimer's disease and autism spectrum disorder.

PMID: 25108264 [PubMed - indexed for MEDLINE]

GABAergic circuit dysfunction in the Drosophila Fragile X syndrome model.

November 14, 2014 - 6:37am
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GABAergic circuit dysfunction in the Drosophila Fragile X syndrome model.

Neurobiol Dis. 2014 May;65:142-59

Authors: Gatto CL, Pereira D, Broadie K

Abstract
Fragile X syndrome (FXS), caused by loss of FMR1 gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 protein (FMRP) translational regulator mediates activity-dependent control of synapses. In addition to the metabotropic glutamate receptor (mGluR) hyperexcitation FXS theory, the GABA theory postulates that hypoinhibition is causative for disease state symptoms. Here, we use the Drosophila FXS model to assay central brain GABAergic circuitry, especially within the Mushroom Body (MB) learning center. All 3 GABAA receptor (GABAAR) subunits are reportedly downregulated in dfmr1 null brains. We demonstrate parallel downregulation of glutamic acid decarboxylase (GAD), the rate-limiting GABA synthesis enzyme, although GABAergic cell numbers appear unaffected. Mosaic analysis with a repressible cell marker (MARCM) single-cell clonal studies show that dfmr1 null GABAergic neurons innervating the MB calyx display altered architectural development, with early underdevelopment followed by later overelaboration. In addition, a new class of extra-calyx terminating GABAergic neurons is shown to include MB intrinsic α/β Kenyon Cells (KCs), revealing a novel level of MB inhibitory regulation. Functionally, dfmr1 null GABAergic neurons exhibit elevated calcium signaling and altered kinetics in response to acute depolarization. To test the role of these GABAergic changes, we attempted to pharmacologically restore GABAergic signaling and assay effects on the compromised MB-dependent olfactory learning in dfmr1 mutants, but found no improvement. Our results show that GABAergic circuit structure and function are impaired in the FXS disease state, but that correction of hypoinhibition alone is not sufficient to rescue a behavioral learning impairment.

PMID: 24423648 [PubMed - indexed for MEDLINE]

Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1.

November 13, 2014 - 3:31pm
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Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1.

Am J Med Genet B Neuropsychiatr Genet. 2014 Nov 12;

Authors: Plasschaert E, Descheemaeker MJ, Van Eylen L, Noens I, Steyaert J, Legius E

Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition. While considerable work has focused on cognitive functioning, several research groups also observed difficulties in social functioning as a prominent feature of NF1. These problems and the possible link between NF1 and Autism Spectrum Disorder (ASD) have become increasingly important in recent NF1 literature. The aim of the current study was to assess ASD characteristics in a hospital-based NF1 pediatric population (n = 82) using the standardized Children Social Behavior Questionnaire (CSBQ) and Social Responsiveness Scale (SRS) to account for the prevalence, severity, and nature of social problems. In a parallel study, comprehensive ASD assessment was performed in a subgroup of NF1 children with a strong suspicion of ASD (n = 31). Results indicate that NF1 children have more social problems than typical controls, more frequently reported above 8 years. The SRS shows that 63% is at risk of ASD symptoms. According to item analyses, most problems were observed on items measuring orientation in, understanding of and being tuned onto a social situation (CSBQ) and social cognition and communication (SRS). In the parallel study, 27 NF1 children were diagnosed with ASD. These children have a distinct phenotype compared to a heterogeneous ASD group, with pronounced social-communicative impairments and fewer restrictive/repetitive behaviors. This study provides a better understanding of social problems in NF1 and the phenotypical overlap with ASD symptomatology. Despite their willingness to engage with others, NF1 children with or without ASD encounter various difficulties in their social-communicative life. © 2014 Wiley Periodicals, Inc.

PMID: 25388972 [PubMed - as supplied by publisher]

Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability.

November 13, 2014 - 3:31pm
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Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability.

PLoS Comput Biol. 2014 Mar;10(3):e1003518

Authors: Rzhetsky A, Bagley SC, Wang K, Lyttle CS, Cook EH, Altman RB, Gibbons RD

Abstract
Many factors affect the risks for neurodevelopmental maladies such as autism spectrum disorders (ASD) and intellectual disability (ID). To compare environmental, phenotypic, socioeconomic and state-policy factors in a unified geospatial framework, we analyzed the spatial incidence patterns of ASD and ID using an insurance claims dataset covering nearly one third of the US population. Following epidemiologic evidence, we used the rate of congenital malformations of the reproductive system as a surrogate for environmental exposure of parents to unmeasured developmental risk factors, including toxins. Adjusted for gender, ethnic, socioeconomic, and geopolitical factors, the ASD incidence rates were strongly linked to population-normalized rates of congenital malformations of the reproductive system in males (an increase in ASD incidence by 283% for every percent increase in incidence of malformations, 95% CI: [91%, 576%], p<6×10(-5)). Such congenital malformations were barely significant for ID (94% increase, 95% CI: [1%, 250%], p = 0.0384). Other congenital malformations in males (excluding those affecting the reproductive system) appeared to significantly affect both phenotypes: 31.8% ASD rate increase (CI: [12%, 52%], p<6×10(-5)), and 43% ID rate increase (CI: [23%, 67%], p<6×10(-5)). Furthermore, the state-mandated rigor of diagnosis of ASD by a pediatrician or clinician for consideration in the special education system was predictive of a considerable decrease in ASD and ID incidence rates (98.6%, CI: [28%, 99.99%], p = 0.02475 and 99% CI: [68%, 99.99%], p = 0.00637 respectively). Thus, the observed spatial variability of both ID and ASD rates is associated with environmental and state-level regulatory factors; the magnitude of influence of compound environmental predictors was approximately three times greater than that of state-level incentives. The estimated county-level random effects exhibited marked spatial clustering, strongly indicating existence of as yet unidentified localized factors driving apparent disease incidence. Finally, we found that the rates of ASD and ID at the county level were weakly but significantly correlated (Pearson product-moment correlation 0.0589, p = 0.00101), while for females the correlation was much stronger (0.197, p<2.26×10(-16)).

PMID: 24625521 [PubMed - indexed for MEDLINE]

Advancing the discovery of medications for autism spectrum disorder using new technologies to reveal social brain circuitry in rodents.

November 13, 2014 - 3:31pm
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Advancing the discovery of medications for autism spectrum disorder using new technologies to reveal social brain circuitry in rodents.

Psychopharmacology (Berl). 2014 Mar;231(6):1147-65

Authors: Kas MJ, Modi ME, Saxe MD, Smith DG

Abstract
INTRODUCTION: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by core differences and impairments in social behavioral functioning. There are no approved medications for improving social cognition and behavior in ASD, and the underlying mechanisms needed to discover safer, more effective medications are unclear.
DISCUSSION: In this review, we diagram the basic neurocircuitry governing social behaviors in order to provide a neurobiological framework for the origins of the core social behavioral symptoms of ASD. In addition, we discuss recent technological innovations in research tools that provide unprecedented observation of cellular morphology and activity deep within the intact brain and permit the precise control of discrete brain regions and specific cell types at distinct developmental stages.
CONCLUSIONS: The use of new technologies to reveal the neural circuits underlying social behavioral impairments associated with ASD is advancing our understanding of the brain changes underlying ASD and enabling the discovery of novel and effective therapeutic interventions.

PMID: 24522332 [PubMed - indexed for MEDLINE]

Neurobiology of autism gene products: towards pathogenesis and drug targets.

November 13, 2014 - 3:31pm
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Neurobiology of autism gene products: towards pathogenesis and drug targets.

Psychopharmacology (Berl). 2014 Mar;231(6):1037-62

Authors: Kleijer KT, Schmeisser MJ, Krueger DD, Boeckers TM, Scheiffele P, Bourgeron T, Brose N, Burbach JP

Abstract
RATIONALE: The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets.
OBJECTIVE: The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms.
METHOD: Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions.
RESULTS: The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity.
CONCLUSIONS: ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.

PMID: 24419271 [PubMed - indexed for MEDLINE]

Using genetic findings in autism for the development of new pharmaceutical compounds.

November 13, 2014 - 3:31pm
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Using genetic findings in autism for the development of new pharmaceutical compounds.

Psychopharmacology (Berl). 2014 Mar;231(6):1063-78

Authors: Vorstman JA, Spooren W, Persico AM, Collier DA, Aigner S, Jagasia R, Glennon JC, Buitelaar JK

Abstract
RATIONALE: The main reason for the current lack of effective treatments for the core symptoms of autism is our limited understanding of the biological mechanisms underlying this heterogeneous group of disorders. A primary value of genetic research is enhancing our insight into the biology of autism through the study of identified autism risk genes.
OBJECTIVES: In the current review we discuss (1) the genes and loci that are associated with autism, (2) how these provide us with essential cues as to what neurobiological mechanisms may be involved, and (3) how these mechanisms may be used as targets for novel treatments. Next, we provide an overview of currently ongoing clinical trials registered at clinicaltrials.gov with a variety of compounds. Finally, we review current approaches used to translate knowledge derived from gene discovery into novel pharmaceutical compounds and discuss their pitfalls and problems.
CONCLUSIONS: An increasing number of genetic variants associated with autism have been identified. This will generate new ideas about the biological mechanisms involved in autism, which in turn may provide new leads for the development of novel pharmaceutical compounds. To optimize this pipeline of drug discovery, large-scale international collaborations are needed for gene discovery, functional validation of risk genes, and improvement of clinical outcome measures and clinical trial methodology in autism.

PMID: 24292384 [PubMed - indexed for MEDLINE]

Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development.

November 13, 2014 - 3:31pm
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Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development.

Psychopharmacology (Berl). 2014 Mar;231(6):1217-26

Authors: Pop AS, Gomez-Mancilla B, Neri G, Willemsen R, Gasparini F

Abstract
RATIONALE: Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents.
OBJECTIVES: This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS.
RESULTS: According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials.
CONCLUSIONS: Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.

PMID: 24232444 [PubMed - indexed for MEDLINE]

Human pluripotent stem cell models of autism spectrum disorder: emerging frontiers, opportunities, and challenges towards neuronal networks in a dish.

November 13, 2014 - 3:31pm
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Human pluripotent stem cell models of autism spectrum disorder: emerging frontiers, opportunities, and challenges towards neuronal networks in a dish.

Psychopharmacology (Berl). 2014 Mar;231(6):1089-104

Authors: Aigner S, Heckel T, Zhang JD, Andreae LC, Jagasia R

Abstract
Autism spectrum disorder (ASD) is characterized by deficits in language development and social cognition and the manifestation of repetitive and restrictive behaviors. Despite recent major advances, our understanding of the pathophysiological mechanisms leading to ASD is limited. Although most ASD cases have unknown genetic underpinnings, animal and human cellular models of several rare, genetically defined syndromic forms of ASD have provided evidence for shared pathophysiological mechanisms that may extend to idiopathic cases. Here, we review our current knowledge of the genetic basis and molecular etiology of ASD and highlight how human pluripotent stem cell-based disease models have the potential to advance our understanding of molecular dysfunction. We summarize landmark studies in which neuronal cell populations generated from human embryonic stem cells and patient-derived induced pluripotent stem cells have served to model disease mechanisms, and we discuss recent technological advances that may ultimately allow in vitro modeling of specific human neuronal circuitry dysfunction in ASD. We propose that these advances now offer an unprecedented opportunity to help better understand ASD pathophysiology. This should ultimately enable the development of cellular models for ASD, allowing drug screening and the identification of molecular biomarkers for patient stratification.

PMID: 24232378 [PubMed - indexed for MEDLINE]

The challenges of clinical trials in fragile X syndrome.

November 13, 2014 - 3:31pm
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The challenges of clinical trials in fragile X syndrome.

Psychopharmacology (Berl). 2014 Mar;231(6):1237-50

Authors: Jacquemont S, Berry-Kravis E, Hagerman R, von Raison F, Gasparini F, Apostol G, Ufer M, Des Portes V, Gomez-Mancilla B

Abstract
RATIONALE: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.
OBJECTIVES: We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.
RESULTS: Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains.
CONCLUSION: Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.

PMID: 24173622 [PubMed - indexed for MEDLINE]

The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders.

November 13, 2014 - 3:31pm
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The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders.

Psychopharmacology (Berl). 2014 Mar;231(6):1079-88

Authors: Cocks G, Curran S, Gami P, Uwanogho D, Jeffries AR, Kathuria A, Lucchesi W, Wood V, Dixon R, Ogilvie C, Steckler T, Price J

Abstract
Until now, models of psychiatric diseases have typically been animal models. Whether they were to be used to further understand the pathophysiology of the disorder, or as drug discovery tools, animal models have been the choice of preference in mimicking psychiatric disorders in an experimental setting. While there have been cellular models, they have generally been lacking in validity. This situation is changing with the advent of patient-specific induced pluripotent stem cells (iPSCs). In this article, we give a methodological evaluation of the current state of the iPS technology with reference to our own work in generating patient-specific iPSCs for the study of autistic spectrum disorder (ASD). In addition, we will give a broader perspective on the validity of this technology and to what extent it can be expected to complement animal models of ASD in the coming years.

PMID: 23839283 [PubMed - indexed for MEDLINE]

Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant.

November 13, 2014 - 3:31pm
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Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant.

Psychopharmacology (Berl). 2014 Mar;231(6):1227-35

Authors: Pop AS, Levenga J, de Esch CE, Buijsen RA, Nieuwenhuizen IM, Li T, Isaacs A, Gasparini F, Oostra BA, Willemsen R

Abstract
Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism. The disease is a result of lack of expression of the fragile X mental retardation protein. Brain tissues of patients with FXS and mice with FMRP deficiency have shown an abnormal dendritic spine phenotype. We investigated the dendritic spine length and density of hippocampal CA1 pyramidal neurons in 2-, 10-, and 25-week-old Fmr1 knockout (KO). Next, we studied the effects of long-term treatment with an mGluR5 antagonist, AFQ056/Mavoglurant, on the spine phenotype in adult Fmr1 KO mice. We observed alterations in the spine phenotype during development, with a decreased spine length in 2-week-old Fmr1 KO mice compared with age-match wild-type littermates, but with increased spine length in Fmr1 KO mice compared with 10- and 25-week-old wild-type controls. No difference was found in spine density at any age. We report a rescue of the abnormal spine length in adult Fmr1 KO mice after a long-term treatment with AFQ056/Mavoglurant. This finding suggests that long-term treatment at later stage is sufficient to reverse the structural spine abnormalities and represents a starting point for future studies aimed at improving treatments for FXS.

PMID: 23254376 [PubMed - indexed for MEDLINE]

Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes.

November 12, 2014 - 8:56am
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Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes.

J Neurosci. 2014 Sep 17;34(38):12877-83

Authors: Sugino K, Hempel CM, Okaty BW, Arnson HA, Kato S, Dani VS, Nelson SB

Abstract
Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome and related autism spectrum disorders (Amir et al., 1999). MeCP2 is believed to be required for proper regulation of brain gene expression, but prior microarray studies in Mecp2 knock-out mice using brain tissue homogenates have revealed only subtle changes in gene expression (Tudor et al., 2002; Nuber et al., 2005; Jordan et al., 2007; Chahrour et al., 2008). Here, by profiling discrete subtypes of neurons we uncovered more dramatic effects of MeCP2 on gene expression, overcoming the "dilution problem" associated with assaying homogenates of complex tissues. The results reveal misregulation of genes involved in neuronal connectivity and communication. Importantly, genes upregulated following loss of MeCP2 are biased toward longer genes but this is not true for downregulated genes, suggesting MeCP2 may selectively repress long genes. Because genes involved in neuronal connectivity and communication, such as cell adhesion and cell-cell signaling genes, are enriched among longer genes, their misregulation following loss of MeCP2 suggests a possible etiology for altered circuit function in Rett syndrome.

PMID: 25232122 [PubMed - indexed for MEDLINE]

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.

November 11, 2014 - 8:41am

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.

Nat Neurosci. 2014 Nov 10;

Authors: Zhang Y, Bonnan A, Bony G, Ferezou I, Pietropaolo S, Ginger M, Sans N, Rossier J, Oostra B, LeMasson G, Frick A

Abstract
Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

PMID: 25383903 [PubMed - as supplied by publisher]

Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population.

November 11, 2014 - 8:41am
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Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population.

J Zhejiang Univ Sci B. 2014 Mar;15(3):264-71

Authors: Liang S, Wang XL, Zou MY, Wang H, Zhou X, Sun CH, Xia W, Wu LJ, Fujisawa TX, Tomoda A

Abstract
OBJECTIVE: A study in a Caucasian population has identified two single-nucleotide polymorphisms (SNPs) in ZNF533, one in DOCK4, and two in IMMP2L, which were all significantly associated with autism. They are located in AUTS1 and AUTS5, which have been identified as autism susceptibility loci in several genome-wide screens. The present study aimed to investigate whether ZNF533, DOCK4, and IMMP2L genes are also associated with autism in a northeastern Chinese Han population.
METHODS: We performed a similar association study using families with three individuals (one autistic child and two unaffected parents). A family-based transmission disequilibrium test (TDT) was used to analyze the results.
RESULTS: There were significant associations between autism and the two SNPs of ZNF533 gene (rs11885327: χ(2)=4.5200, P=0.0335; rs1964081: χ(2)=4.2610, P=0.0390) and the SNP of DOCK4 gene (rs2217262: χ(2)=5.3430, P=0.0208).
CONCLUSIONS: Our data suggest that ZNF533 and DOCK4 genes are linked to a predisposition to autism in the northeastern Chinese Han population.

PMID: 24599690 [PubMed - indexed for MEDLINE]

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