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The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations.

June 27, 2014 - 8:12am
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The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations.

Behav Brain Res. 2013 Nov 1;256:677-89

Authors: Ey E, Torquet N, Le Sourd AM, Leblond CS, Boeckers TM, Faure P, Bourgeron T

Abstract
Mouse ultrasonic vocalisations have been often used as a paradigm to extrapolate vocal communication defects observed in patients with autism spectrum disorders (ASD). The role of these vocalisations as well as their development, structure and informational content, however, remain largely unknown. In the present study, we characterised in depth the emission of pup and adult ultrasonic vocalisations of wild-type mice and their ProSAP1/Shank2(-/-) littermates lacking a synaptic scaffold protein mutated in ASD. We hypothesised that the vocal behaviour of ProSAP1/Shank2(-/-) mice not only differs from the vocal behaviour of their wild-type littermates in a quantitative way, but also presents more qualitative abnormalities in temporal organisation and acoustic structure. We first quantified the rate of emission of ultrasonic vocalisations, and analysed the organisation of vocalisations sequences using Markov models. We subsequently measured duration and peak frequency characteristics of each ultrasonic vocalisation, to characterise their acoustic structure. In wild-type mice, we found a high level of organisation in sequences of ultrasonic vocalisations, suggesting a communicative function in this complex system. Very limited significant sex-related variations were detected in their usage and acoustic structure, even in adult mice. In adult ProSAP1/Shank2(-/-) mice, we found abnormalities in the call usage and the structure of ultrasonic vocalisations. Both ProSAP1/Shank2(-/-) male and female mice uttered less vocalisations with a different call distribution and at lower peak frequency in comparison with wild-type littermates. This study provides a comprehensive framework to characterise abnormalities of ultrasonic vocalisations in mice and confirms that ProSAP1/Shank2(-/-) mice represent a relevant model to study communication defects.

PMID: 23994547 [PubMed - indexed for MEDLINE]

Mutational Analyses of the FMR1 Gene in Chinese Pediatric Population of Fragile X Suspects: Low Tolerance for Point Mutation.

June 26, 2014 - 8:03am

Mutational Analyses of the FMR1 Gene in Chinese Pediatric Population of Fragile X Suspects: Low Tolerance for Point Mutation.

J Child Neurol. 2014 Jun 23;

Authors: Luo S, Huang W, Xia Q, Du Q, Wu L, Duan R

Abstract
CGG repeat expansion is the most common cause of fragile X syndrome. Numerous efforts have been made to identify novel mutations in patients with intellectual disability, developmental delay, and/or autism. To evaluate the mutational spectrum in the at-risk Chinese population, 60 pediatric patients presenting fragile X traits but normal-sized CGG repeats were sequenced for all 17 exons and regulatory regions in FMR1. A c.879A>C mutation, reported to alter a neighboring splicing, was detected in a severely retarded male and his normal mother. However, the exon junction appears unaffected. A 237-kb deletion covering the entire FMR1 was identified to cause moderate intellectual disability and marked hyperactivity in an 8-year-old boy. The 5' and 3' breakpoints were buried in the surrounding long interspersed and short interspersed elements, respectively. In general, missense mutations do not commonly cause fragile X syndrome, whereas deletions should be considered with caution in patient referrals presenting with developmental delay and/or ordinary retardation.

PMID: 24963073 [PubMed - as supplied by publisher]

Developmental changes in expression of inhibitory neuronal proteins in the Fragile X Syndrome mouse basolateral amygdala.

June 26, 2014 - 8:03am
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Developmental changes in expression of inhibitory neuronal proteins in the Fragile X Syndrome mouse basolateral amygdala.

Brain Res. 2013 Nov 6;1537:69-78

Authors: Kratovac S, Corbin JG

Abstract
In humans, Fragile X Syndrome (FXS) is characterized by enhanced fear, hyperactivity, social anxiety, and, in a subset of individuals, autism. Many of the emotional and social deficits point to defects in the amygdala. We have previously shown defects in inhibitory neuron drive onto excitatory projection neurons in the basolateral amygdala (BLA) of juvenile Fmr1(-/y) knockout (KO) mice. Using pharmacological approaches, we have also previously revealed dynamic functional deficits in α1, α2, and α3 subunit-containing GABAA receptors (GABAARs α1, α2, and α3) during early postnatal development. In this study, we sought to determine whether these defects in GABAAR function are accompanied by changes in protein expression of GABAARs α1, α2, and α3 and the post-synaptic GABAAR-clustering protein gephyrin. Interestingly, we found that while the expression of these proteins did not significantly differ between wildtype (WT) and KO mice at each time point, the timing of developmental expression of GABAAR α1, α2, and gephyrin was altered. Collectively, these data reveal novel defects in inhibitory synapse protein expression during critical periods of early postnatal development that could contribute to observed inhibitory neurotransmission deficits in the KO mouse BLA.

PMID: 24008143 [PubMed - indexed for MEDLINE]

Chromosome 15q11-q13 copy number gain detected by array-CGH in two cases with a maternal methylation pattern.

June 25, 2014 - 7:44am

Chromosome 15q11-q13 copy number gain detected by array-CGH in two cases with a maternal methylation pattern.

Mol Cytogenet. 2014;7:32

Authors: Tan ES, Yong MH, Lim EC, Li ZH, Brett MS, Tan EC

Abstract
BACKGROUND: The 15q11-q13 region contains many low copy repeats and is well known for its genomic instability. Several syndromes are associated with genomic imbalance or copy-number-neutral uniparental disomy. We report on two patients: Patient 1 is a boy with developmental delay and autism; and Patient 2 is a girl with developmental delay, hypotonia and dysmorphism. We performed analyses to delineate their dosage in the 15q region, determine whether the patients' dosage correlates with phenotypic severity, and whether genes in the amplified regions are significantly associated with identified functional networks.
RESULTS: For the proximal region of 15q, molecular cytogenetic analysis with Agilent oligonucleotide array showed a copy number of 3 for Patient 1 and a copy number of 4 for Patient 2. Fluorescent in situ hybridization analysis of Patient 2 showed two different populations of cells with different marker chromosomes. Methylation analysis of the amplified region showed that the extra copies of small nuclear ribonucleoprotein polypeptide N gene were of maternal origin. Phenotypic severity did not correlate with the size and dosage of 15q, or whether the amplification is interstitial or in the form of a supernumerary marker. Pathway analysis showed that in Patient 2, the main functional networks that are affected by the genes from the duplicated/triplicated regions are developmental disorder, neurological disease and hereditary disease.
CONCLUSIONS: The 15q11-q13 gains that were found in both patients could explain their phenotypic presentations. This report expands the cohort of patients for which 15q11-q13 duplications are molecularly characterized.

PMID: 24959201 [PubMed]

Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified.

June 25, 2014 - 7:44am
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Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified.

PLoS One. 2013;8(10):e76993

Authors: De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, Cristofori F, Guerzoni ME, Gobbetti M, Francavilla R

Abstract
This study aimed at investigating the fecal microbiota and metabolome of children with Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) and autism (AD) in comparison to healthy children (HC). Bacterial tag-encoded FLX-titanium amplicon pyrosequencing (bTEFAP) of the 16S rDNA and 16S rRNA analyses were carried out to determine total bacteria (16S rDNA) and metabolically active bacteria (16S rRNA), respectively. The main bacterial phyla (Firmicutes, Bacteroidetes, Fusobacteria and Verrucomicrobia) significantly (P<0.05) changed among the three groups of children. As estimated by rarefaction, Chao and Shannon diversity index, the highest microbial diversity was found in AD children. Based on 16S-rRNA and culture-dependent data, Faecalibacterium and Ruminococcus were present at the highest level in fecal samples of PDD-NOS and HC children. Caloramator, Sarcina and Clostridium genera were the highest in AD children. Compared to HC, the composition of Lachnospiraceae family also differed in PDD-NOS and, especially, AD children. Except for Eubacterium siraeum, the lowest level of Eubacteriaceae was found on fecal samples of AD children. The level of Bacteroidetes genera and some Alistipes and Akkermansia species were almost the highest in PDD-NOS or AD children as well as almost all the identified Sutterellaceae and Enterobacteriaceae were the highest in AD. Compared to HC children, Bifidobacterium species decreased in AD. As shown by Canonical Discriminant Analysis of Principal Coordinates, the levels of free amino acids and volatile organic compounds of fecal samples were markedly affected in PDD-NOS and, especially, AD children. If the gut microbiota differences among AD and PDD-NOS and HC children are one of the concomitant causes or the consequence of autism, they may have implications regarding specific diagnostic test, and/or for treatment and prevention.

PMID: 24130822 [PubMed - indexed for MEDLINE]

Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism.

June 25, 2014 - 7:44am
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Role of conserved cis-regulatory elements in the post-transcriptional regulation of the human MECP2 gene involved in autism.

Hum Genomics. 2013;7:19

Authors: Bagga JS, D'Antonio LA

Abstract
BACKGROUND: The MECP2 gene codes for methyl CpG binding protein 2 which regulates activities of other genes in the early development of the brain. Mutations in this gene have been associated with Rett syndrome, a form of autism. The purpose of this study was to investigate the role of evolutionarily conserved cis-elements in regulating the post-transcriptional expression of the MECP2 gene and to explore their possible correlations with a mutation that is known to cause mental retardation.
RESULTS: A bioinformatics approach was used to map evolutionarily conserved cis-regulatory elements in the transcribed regions of the human MECP2 gene and its mammalian orthologs. Cis-regulatory motifs including G-quadruplexes, microRNA target sites, and AU-rich elements have gained significant importance because of their role in key biological processes and as therapeutic targets. We discovered in the 5'-UTR (untranslated region) of MECP2 mRNA a highly conserved G-quadruplex which overlapped a known deletion in Rett syndrome patients with decreased levels of MeCP2 protein. We believe that this 5'-UTR G-quadruplex could be involved in regulating MECP2 translation. We mapped additional evolutionarily conserved G-quadruplexes, microRNA target sites, and AU-rich elements in the key sections of both untranslated regions. Our studies suggest the regulation of translation, mRNA turnover, and development-related alternative MECP2 polyadenylation, putatively involving interactions of conserved cis-regulatory elements with their respective trans factors and complex interactions among the trans factors themselves. We discovered highly conserved G-quadruplex motifs that were more prevalent near alternative splice sites as compared to the constitutive sites of the MECP2 gene. We also identified a pair of overlapping G-quadruplexes at an alternative 5' splice site that could potentially regulate alternative splicing in a negative as well as a positive way in the MECP2 pre-mRNAs.
CONCLUSIONS: A Rett syndrome mutation with decreased protein expression was found to be associated with a conserved G-quadruplex. Our studies suggest that MECP2 post-transcriptional gene expression could be regulated by several evolutionarily conserved cis-elements like G-quadruplex motifs, microRNA target sites, and AU-rich elements. This phylogenetic analysis has provided some interesting and valuable insights into the regulation of the MECP2 gene involved in autism.

PMID: 24040966 [PubMed - indexed for MEDLINE]

Biological overlap of attention-deficit/hyperactivity disorder and autism spectrum disorder: evidence from copy number variants.

June 24, 2014 - 7:37am

Biological overlap of attention-deficit/hyperactivity disorder and autism spectrum disorder: evidence from copy number variants.

J Am Acad Child Adolesc Psychiatry. 2014 Jul;53(7):761-770.e26

Authors: Martin J, Cooper M, Hamshere ML, Pocklington A, Scherer SW, Kent L, Gill M, Owen MJ, Williams N, O'Donovan MC, Thapar A, Holmans P

Abstract
OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings.
METHOD: We compared copy number variant (CNV) data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. Using pathway analyses, we investigated whether CNVs observed in individuals with ADHD have an impact on genes in the same biological pathways as on those observed in individuals with ASD.
RESULTS: The results suggest that the biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Moreover, this was true even when specific CNV regions common to both disorders were excluded from the analysis. After correction for multiple testing, genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample.
CONCLUSION: The results of this study indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions.

PMID: 24954825 [PubMed - in process]

Neurodevelopmental Disorders and Prenatal Residential Proximity to Agricultural Pesticides: The CHARGE Study.

June 24, 2014 - 7:37am

Neurodevelopmental Disorders and Prenatal Residential Proximity to Agricultural Pesticides: The CHARGE Study.

Environ Health Perspect. 2014 Jun 23;

Authors: Shelton JF, Geraghty EM, Tancredi DJ, Delwiche LD, Schmidt RJ, Ritz B, Hansen RL, Hertz-Picciotto I

Abstract
BACKGROUND: Gestational exposure to several common agricultural pesticides can induce developmental neurotoxicity in humans, and has been associated with developmental delay and autism.
OBJECTIVES: To evaluate whether residential proximity to agricultural pesticides during pregnancy is associated with autism spectrum disorders (ASD) or developmental delay (DD) in the Childhood Autism Risks from Genetics and Environment (CHARGE) Study.
METHODS: The CHARGE study is a population-based case-control study of ASD, developmental delay (DD), and typical development. For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997-2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25km, 1.5km, and 1.75km buffer distances from the home. Multinomial logistic regression was used to estimate the odds ratio (OR) of exposure comparing confirmed cases of ASD (n = 486) or DD (n = 168) with typically developing referents (n = 316).
RESULTS: Approximately one-third of CHARGE Study mothers lived, during pregnancy, within 1.5 km (just under one mile) of an agricultural pesticide application. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for 3(rd) trimester exposures [OR = 2.0, 95% confidence interval (CI) = (1.1, 3.6)], and 2(nd) trimester chlorpyrifos applications: OR = 3.3 [95% CI = (1.5, 7.4)]. Children of mothers residing near pyrethroid insecticide applications just prior to conception or during 3rd trimester were at greater risk for both ASD and DD, with OR's ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified.
CONCLUSIONS: This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, and particularly, organophosphates and provides novel results of ASD and DD associations with, respectively, pyrethroids and carbamates.

PMID: 24954055 [PubMed - as supplied by publisher]

Drosophila melanogaster: a novel animal model for the behavioral characterization of autism-associated mutations in the dopamine transporter gene.

June 24, 2014 - 7:37am
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Drosophila melanogaster: a novel animal model for the behavioral characterization of autism-associated mutations in the dopamine transporter gene.

Mol Psychiatry. 2013 Dec;18(12):1235

Authors: Hamilton PJ, Campbell NG, Sharma S, Erreger K, Hansen FH, Saunders C, Belovich AN, Sahai MA, Cook EH, Gether U, McHaourab HS, Matthies HJ, Sutcliffe JS, Galli A

PMID: 24253181 [PubMed - indexed for MEDLINE]

Psychiatric assessment of severe presentations in autism spectrum disorders and intellectual disability.

June 24, 2014 - 7:37am
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Psychiatric assessment of severe presentations in autism spectrum disorders and intellectual disability.

Child Adolesc Psychiatr Clin N Am. 2014 Jan;23(1):1-14

Authors: King BH, de Lacy N, Siegel M

Abstract
Children with autism spectrum and related disorders and intellectual disability are not protected from the experience of psychiatric illnesses. Many factors can contribute to exacerbation of existing behavioral symptoms or to the emergence of new psychiatric problems. The psychiatric assessment must thus take into account a range of possible etiologic or contributory factors. The approach outlined in this article highlights the value of assessing 4 broad domains, including diagnostic (genetic) factors, medical considerations, developmental influences, and environmental factors. Examples of how the consideration of each of these domains may inform the diagnostic formulation are highlighted.

PMID: 24231163 [PubMed - indexed for MEDLINE]

Typical and atypical brain development: a review of neuroimaging studies.

June 24, 2014 - 7:37am
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Typical and atypical brain development: a review of neuroimaging studies.

Dialogues Clin Neurosci. 2013 Sep;15(3):359-84

Authors: Dennis EL, Thompson PM

Abstract
In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders.

PMID: 24174907 [PubMed - indexed for MEDLINE]

Neuroligin modulates the locomotory dopaminergic and serotonergic neuronal pathways of C. elegans.

June 24, 2014 - 7:37am
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Neuroligin modulates the locomotory dopaminergic and serotonergic neuronal pathways of C. elegans.

Neurogenetics. 2013 Nov;14(3-4):233-42

Authors: Izquierdo PG, Calahorro F, Ruiz-Rubio M

Abstract
Neuroligins are neuronal and neuromuscular transmembrane proteins that have been implicated in autism spectrum disorder and other cognitive diseases. The nlg-1 gene from Caenorhabditis elegans is orthologous to human neuroligin genes. In the nematode, the locomotory rate is mediated by dopaminergic and serotonergic pathways, which result in two different behavioral responses known as basal slowing response (BSR) and enhanced slowing response (ESR), respectively. We report that nlg-1-deficient mutants are defective in both the BSR and ESR behaviors. In addition, we demonstrate that methylphenidate (a dopamine reuptake inhibitor) and fluoxetine (a serotonin reuptake inhibitor), two drugs widely used for the treatment of behavioral disorders in humans, are able to restore the BSR and ESR wild type phenotypes, respectively, in nlg-1 defective mutant nematodes. The abnormal locomotory behavior patterns were rescued in nlg-1-deficient mutant by expressing a cDNA from the human NLGN1 gene under the C. elegans nlg-1 promoter. However, human NLGN1 (R453C) and NLGN1 (D432X) mutant alleles did not rescue any of the two mutant phenotypes. The results indicate that neuroligin is involved in modulating the action of dopamine and serotonin in the nematode and suggest that the functional mechanism underpinning both methylphenidate and fluoxetine in C. elegans might be comparable to that in humans. The neuroligin-deficient mutants may undergo inefficient synaptic transmissions which could affect different traits in the nervous system. In particular, neuroligin might be required for normal neurotransmitters release. The understanding of the mechanisms by which methylphenidate and fluoxetine are able to restore the behavior of these mutants could help to explain the etiology of some human neurological diseases.

PMID: 24100941 [PubMed - indexed for MEDLINE]

Benign infantile convulsions (IC) and subsequent paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome.

June 24, 2014 - 7:37am
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Benign infantile convulsions (IC) and subsequent paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome.

Neurogenetics. 2013 Nov;14(3-4):251-3

Authors: Weber A, Köhler A, Hahn A, Neubauer B, Müller U

Abstract
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is caused by mutations in the gene PRRT2 located in 16p11.2. A deletion syndrome 16p11.2 is well established and is characterized by intellectual disability, speech delay, and autism. PKD/IC, however, is extremely rare in this syndrome. We describe a case of PKD/IC and 16p11.2 deletion syndrome and discuss modifiers of PRRT2 activity to explain the rare concurrence of both syndromes.

PMID: 24100940 [PubMed - indexed for MEDLINE]

The social defeat hypothesis of schizophrenia: an update.

June 24, 2014 - 7:37am
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The social defeat hypothesis of schizophrenia: an update.

Schizophr Bull. 2013 Nov;39(6):1180-6

Authors: Selten JP, van der Ven E, Rutten BP, Cantor-Graae E

Abstract
According to the social defeat (SD) hypothesis, published in 2005, long-term exposure to the experience of SD may lead to sensitization of the mesolimbic dopamine (DA) system and thereby increase the risk for schizophrenia. The hypothesis posits that SD (ie, the negative experience of being excluded from the majority group) is the common denominator of 5 major schizophrenia risk factors: urban upbringing, migration, childhood trauma, low intelligence, and drug abuse. The purpose of this update of the literature since 2005 is to answer 2 questions: (1) What is the evidence that SD explains the association between schizophrenia and these risk factors? (2) What is the evidence that SD leads to sensitization of the mesolimbic DA system? The evidence for SD as the mechanism underlying the increased risk was found to be strongest for migration and childhood trauma, while the evidence for urban upbringing, low intelligence, and drug abuse is suggestive, but insufficient. Some other findings that may support the hypothesis are the association between risk for schizophrenia and African American ethnicity, unemployment, single status, hearing impairment, autism, illiteracy, short stature, Klinefelter syndrome, and, possibly, sexual minority status. While the evidence that SD in humans leads to sensitization of the mesolimbic DA system is not sufficient, due to lack of studies, the evidence for this in animals is strong. The authors argue that the SD hypothesis provides a parsimonious and plausible explanation for a number of epidemiological findings that cannot be explained solely by genetic confounding.

PMID: 24062592 [PubMed - indexed for MEDLINE]

De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.

June 24, 2014 - 7:37am
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De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.

Mol Psychiatry. 2013 Dec;18(12):1315-23

Authors: Hamilton PJ, Campbell NG, Sharma S, Erreger K, Herborg Hansen F, Saunders C, Belovich AN, NIH ARRA Autism Sequencing Consortium, Sahai MA, Cook EH, Gether U, McHaourab HS, Matthies HJ, Sutcliffe JS, Galli A

Abstract
De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions.

PMID: 23979605 [PubMed - indexed for MEDLINE]

Effects of environmental enrichment on repetitive behaviors in the BTBR T+tf/J mouse model of autism.

June 21, 2014 - 6:09am
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Effects of environmental enrichment on repetitive behaviors in the BTBR T+tf/J mouse model of autism.

Autism Res. 2013 Oct;6(5):337-43

Authors: Reynolds S, Urruela M, Devine DP

Abstract
Lower order and higher order repetitive behaviors have been documented in the BTBR T+tf/J (BTBR) mouse strain, a mouse model that exhibits all three core behavioral domains that define autism. The purpose of this study was to evaluate the effectiveness of environmental enrichment for reducing repetitive behaviors in BTBR mice. Lower order behaviors were captured by assaying the time and sequence of grooming, while higher order behaviors were measured using pattern analysis of an object exploration task from digital recordings. Baseline scores were established at 7 weeks of age, followed by 30 days of housing in either a standard or enriched cage. As expected, BTBR mice spent significantly more time grooming and had a more rigid grooming sequence than control C57BL/6J mice did at baseline. After 30 days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming, resulting in levels that were lower than those exhibited by BTBR mice in standard housing. However, no changes were noted in the rigidity of their grooming sequence. In contrast to previous findings, there was no difference in repetitive patterns of exploration at baseline between BTBR and C57BL/6J mice in the object exploration test. Subsequently, enrichment did not significantly alter the number of repetitive patterns at posttest. Overall, the results suggest that environmental enrichment may be beneficial for reducing the time spent engaging in lower order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest.

PMID: 23813950 [PubMed - indexed for MEDLINE]

Stem cells as a good tool to investigate dysregulated biological systems in autism spectrum disorders.

June 21, 2014 - 6:09am
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Stem cells as a good tool to investigate dysregulated biological systems in autism spectrum disorders.

Autism Res. 2013 Oct;6(5):354-61

Authors: Griesi-Oliveira K, Sunaga DY, Alvizi L, Vadasz E, Passos-Bueno MR

Abstract
Identification of the causes of autism spectrum disorders (ASDs) is hampered by their genetic heterogeneity; however, the different genetic alterations leading to ASD seem to be implicated in the disturbance of common molecular pathways or biological processes. In this scenario, the search for differentially expressed genes (DEGs) between ASD patients and controls is a good alternative to identify the molecular etiology of such disorders. Here, we employed genome-wide expression analysis to compare the transcriptome of stem cells of human exfoliated deciduous teeth (SHEDs) of idiopathic autistic patients (n = 7) and control samples (n = 6). Nearly half of the 683 identified DEGs are expressed in the brain (P = 0.003), and a significant number of them are involved in mechanisms previously associated with ASD such as protein synthesis, cytoskeleton regulation, cellular adhesion and alternative splicing, which validate the use of SHEDs to disentangle the causes of autism. Autistic patients also presented overexpression of genes regulated by androgen receptor (AR), and AR itself, which in turn interacts with CHD8 (chromodomain helicase DNA binding protein 8), a gene recently shown to be associated with the cause of autism and found to be upregulated in some patients tested here. These data provide a rationale for the mechanisms through which CHD8 leads to these diseases. In summary, our results suggest that ASD share deregulated pathways and revealed that SHEDs represent an alternative cell source to be used in the understanding of the biological mechanisms involved in the etiology of ASD.

PMID: 23801657 [PubMed - indexed for MEDLINE]

Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.

June 21, 2014 - 6:09am
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Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.

Autism Res. 2013 Oct;6(5):384-92

Authors: Pu D, Shen Y, Wu J

Abstract
Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism.

PMID: 23653228 [PubMed - indexed for MEDLINE]

Network Plasticity in Adaptive Filtering and Behavioral Habituation.

June 20, 2014 - 8:08am

Network Plasticity in Adaptive Filtering and Behavioral Habituation.

Neuron. 2014 Jun 18;82(6):1216-1229

Authors: Ramaswami M

Abstract
The ability of organisms to seamlessly ignore familiar, inconsequential stimuli improves their selective attention and response to salient features of the environment. Here, I propose that this fundamental but unexplained phenomenon substantially derives from the ability of any pattern of neural excitation to create an enhanced inhibitory (or "negative") image of itself through target-specific scaling of inhibitory inputs onto active excitatory neurons. Familiar stimuli encounter strong negative images and are therefore less likely to be transmitted to higher brain centers. Integrating historical and recent observations, the negative-image model described here provides a mechanistic framework for understanding habituation, which is connected to ideas on dynamic predictive coding. In addition, it suggests insights for understanding autism spectrum disorders. VIDEO ABSTRACT:

PMID: 24945768 [PubMed - as supplied by publisher]

Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice.

June 20, 2014 - 8:08am

Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice.

Genome Med. 2014;6(4):29

Authors: Doherty JL, Owen MJ

Abstract
Psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder and autism spectrum disorder are common and result in significant morbidity and mortality. Although currently classified into distinct disorder categories, they show clinical overlap and familial co-aggregation, and share genetic risk factors. Recent advances in psychiatric genomics have provided insight into the potential mechanisms underlying the overlap between these disorders, implicating genes involved in neurodevelopment, synaptic plasticity, learning and memory. Furthermore, evidence from copy number variant, exome sequencing and genome-wide association studies supports a gradient of neurodevelopmental psychopathology indexed by mutational load or mutational severity, and cognitive impairment. These findings have important implications for psychiatric research, highlighting the need for new approaches to stratifying patients for research. They also point the way for work aiming to advance our understanding of the pathways from genotype to clinical phenotype, which will be required in order to inform new classification systems and to develop novel therapeutic strategies.

PMID: 24944580 [PubMed - as supplied by publisher]

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