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Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies.

December 3, 2014 - 8:29am

Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies.

Mol Genet Metab. 2014 Oct 12;

Authors: Ramaekers VT, Thöny B, Sequeira JM, Ansseau M, Philippe P, Boemer F, Bours V, Quadros EV

Abstract
BACKGROUND: Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide.
METHODS: Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated.
RESULTS: Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ(2)=21.6; p<0.0001). FRα antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean±SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement.
CONCLUSION: Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process.

PMID: 25456743 [PubMed - as supplied by publisher]

Language Impairment and Dyslexia Genes Influence Language Skills in Children With Autism Spectrum Disorders.

December 3, 2014 - 8:29am

Language Impairment and Dyslexia Genes Influence Language Skills in Children With Autism Spectrum Disorders.

Autism Res. 2014 Dec 1;

Authors: Eicher JD, Gruen JR

Abstract
Language and communication development is a complex process influenced by numerous environmental and genetic factors. Many neurodevelopment disorders include deficits in language and communication skills in their diagnostic criteria, including autism spectrum disorders (ASD), language impairment (LI), and dyslexia. These disorders are polygenic and complex with a significant genetic component contributing to each. The similarity of language phenotypes and comorbidity of these disorders suggest that they may share genetic contributors. To test this, we examined the association of genes previously implicated in dyslexia, LI, and/or language-related traits with language skills in children with ASD. We used genetic and language data collected in the Autism Genome Research Exchange (AGRE) and Simons Simplex Collection (SSC) cohorts to perform a meta-analysis on performance on a receptive vocabulary task. There were associations with LI risk gene ATP2C2 and dyslexia risk gene MRPL19. Additionally, we found suggestive evidence of association with CMIP, GCFC2, KIAA0319L, the DYX2 locus (ACOT13, GPLD1, and FAM65B), and DRD2. Our results show that LI and dyslexia genes also contribute to language traits in children with ASD. These associations add to the growing literature of generalist genes that contribute to multiple related neurobehavioral traits. Future studies should examine whether other genetic contributors may be shared among these disorders and how risk variants interact with each other and the environment to modify clinical presentations. Autism Res 2014, ●●; ●●-●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 25448322 [PubMed - as supplied by publisher]

Toward an immune-mediated subtype of autism spectrum disorder.

December 3, 2014 - 8:29am

Toward an immune-mediated subtype of autism spectrum disorder.

Brain Res. 2014 Nov 13;

Authors: McDougle CJ, Landino SM, Vahabzadeh A, O'Rourke J, Zurcher NR, Finger BC, Palumbo ML, Helt J, Mullett JE, Hooker JM, Carlezon WA

Abstract
A role for immunological involvement in autism spectrum disorder (ASD) has long been hypothesized. This review includes four sections describing (1) evidence for a relationship between familial autoimmune disorders and ASD; (2) results from post-mortem and neuroimaging studies that investigated aspects of neuroinflammation in ASD; (3) findings from animal model work in ASD involving inflammatory processes; and (4) outcomes from trials of anti-inflammatory/immunemodulating drugs in ASD that have appeared in the literature. Following each section, ideas are provided for future research, suggesting paths forward in the continuing effort to define the role of immune factors and inflammation in the pathophysiology of a subtype of ASD.

PMID: 25445995 [PubMed - as supplied by publisher]

Social visual engagement in infants and toddlers with autism: Early developmental transitions and a model of pathogenesis.

December 3, 2014 - 8:29am

Social visual engagement in infants and toddlers with autism: Early developmental transitions and a model of pathogenesis.

Neurosci Biobehav Rev. 2014 Oct 16;

Authors: Klin A, Shultz S, Jones W

Abstract
Efforts to determine and understand the causes of autism are currently hampered by a large disconnect between recent molecular genetics findings that are associated with the condition and the core behavioral symptoms that define the condition. In this perspective piece, we propose a systems biology framework to bridge that gap between genes and symptoms. The framework focuses on basic mechanisms of socialization that are highly-conserved in evolution and are early-emerging in development. By conceiving of these basic mechanisms of socialization as quantitative endophenotypes, we hope to connect genes and behavior in autism through integrative studies of neurodevelopmental, behavioral, and epigenetic changes. These changes both lead to and are led by the accomplishment of specific social adaptive tasks in a typical infant's life. However, based on recent research that indicates that infants later diagnosed with autism fail to accomplish at least some of these tasks, we suggest that a narrow developmental period, spanning critical transitions from reflexive, subcortically-controlled visual behavior to interactional, cortically-controlled and social visual behavior be prioritized for future study. Mapping epigenetic, neural, and behavioral changes that both drive and are driven by these early transitions may shed a bright light on the pathogenesis of autism.

PMID: 25445180 [PubMed - as supplied by publisher]

Fragile X-like behaviors and abnormal cortical dendritic spines in Cytoplasmic FMR1 interacting protein 2 mutant mice.

November 30, 2014 - 8:08am

Fragile X-like behaviors and abnormal cortical dendritic spines in Cytoplasmic FMR1 interacting protein 2 mutant mice.

Hum Mol Genet. 2014 Nov 28;

Authors: Han K, Chen H, Gennarino VA, Richman R, Lu HC, Zoghbi HY

Abstract
Silencing of fragile X mental retardation 1 (FMR1) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1 interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here we generated and characterized Cyfip2 mutant (Cyfip2(+/-)) mice. We found that Cyfip2(+/-) mice exhibited behavioral phenotypes similar to Fmr1 null (Fmr1(-/y)) mice, an animal model of fragile X syndrome. Synaptic plasticity and dendritic spines were normal in Cyfip2(+/-) hippocampus. However, dendritic spines were altered in Cyfip2(+/-) cortex, and the dendritic spine phenotype of Fmr1(-/y) cortex was aggravated in Fmr1(-/y);Cyfip2(+/-) double mutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1(-/y) and Cyfip2(+/-) cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in Fmr1(-/y) or Cyfip2(+/-) neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS.

PMID: 25432536 [PubMed - as supplied by publisher]

MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders.

November 29, 2014 - 7:51am

MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders.

Genet Res Int. 2014;2014:698574

Authors: Sener EF, Oztop DB, Ozkul Y

Abstract
Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism.

PMID: 25431675 [PubMed - as supplied by publisher]

Activity-Dependent Neuroprotective Protein (ADNP): A Case Study for Highly Conserved Chordata-Specific Genes Shaping the Brain and Mutated in Cancer.

November 28, 2014 - 7:44am

Activity-Dependent Neuroprotective Protein (ADNP): A Case Study for Highly Conserved Chordata-Specific Genes Shaping the Brain and Mutated in Cancer.

J Alzheimers Dis. 2014 Nov 25;

Authors: Gozes I, Yeheskel A, Pasmanik-Chor M

Abstract
The recent finding of activity-dependent neuroprotective protein (ADNP) as a protein decreased in serum of patients with Alzheimer's disease (AD) compared to controls, alongside with the discovery of ADNP mutations in autism and coupled with the original description of cancer mutations, ignited an interest for a comparative analysis of ADNP with other AD/autism/cancer-associated genes. We strive toward a better understanding of the molecular structure of key players in psychiatric/neurodegenerative diseases including autism, schizophrenia, and AD. This article includes data mining and bioinformatics analysis on the ADNP gene and protein, in addition to other related genes, with emphasis on recent literature. ADNP is discovered here as unique to chordata with specific autism mutations different from cancer-associated mutation. Furthermore, ADNP exhibits similarities to other cancer/autism-associated genes. We suggest that key genes, which shape and maintain our brain and are prone to mutations and are by in large unique to chordata. Furthermore, these brain-controlling genes, like ADNP, are linked to cell growth and differentiation, and under different stress conditions may mutate or exhibit expression changes leading to cancer propagation. Better understanding of these genes could lead to better therapeutics.

PMID: 25428252 [PubMed - as supplied by publisher]

Human FMRP contains an integral tandem Agenet (Tudor) and KH motif in the amino terminal domain.

November 25, 2014 - 7:22am

Human FMRP contains an integral tandem Agenet (Tudor) and KH motif in the amino terminal domain.

Hum Mol Genet. 2014 Nov 20;

Authors: Myrick LK, Hashimoto H, Cheng X, Warren ST

Abstract
Fragile X syndrome, a common cause of intellectual disability and autism, is due to mutational silencing of the FMR1 gene leading to the absence of its gene product, FMRP. FMRP is a selective RNA-binding protein owing to two central KH domains and a C-terminal RGG box. However, several properties of the FMRP amino terminus are unresolved. It has been documented for over a decade that the amino terminus has the ability to bind RNA despite having no recognizable functional motifs. Moreover, the amino terminus has recently been shown to bind chromatin and influence the DNA damage response as well as function in the presynaptic space, modulating action potential duration. We report here the amino terminal crystal structures of wild-type FMRP, and a mutant (R138Q) that disrupts the amino terminus function, containing an integral tandem Agenet and discover a novel KH motif.

PMID: 25416280 [PubMed - as supplied by publisher]

Personality development and intellectual disability.

November 22, 2014 - 6:39pm

Personality development and intellectual disability.

Curr Opin Psychiatry. 2014 Nov 19;

Authors: Roy M, Retzer A, Sikabofori T

Abstract
PURPOSE OF REVIEW: This review examines the factors that shape personality and how they can inform on the behaviour of people with intellectual disability both to help them function at least at their cognitive level and add a developmental dimension to treatment plans.
RECENT FINDINGS: People with intellectual disability experience more failure, rejection and social deprivation leading to personality traits that may impede their ability to learn and predispose them to depression. Brain changes due to genetic conditions may be responsible for the behavioural phenotypes, although the autism phenotype is associated with different causes. Schizophrenia has a strong neurodevelopmental component and it could be on a gradient of decreasing neurodevelopmental impairment between intellectual disability and autism on one hand and bipolar disorder on the other.
SUMMARY: Understanding how early-life experience and current-life situations give rise to personality traits and taking a developmental perspective, for example, mental age, could clarify the clinical presentation. Developments in molecular genetics and brain imaging may clarify how brain changes lead to personality features. Finally, it may be time to address whether it is still helpful to have categorical diagnoses when there is increasing evidence from genetic studies supporting a continuum of neurodevelopmental disorders.

PMID: 25415494 [PubMed - as supplied by publisher]

Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders.

November 22, 2014 - 6:39pm

Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders.

Front Neurosci. 2014;8:331

Authors: Lotan A, Fenckova M, Bralten J, Alttoa A, Dixson L, Williams RW, van der Voet M

Abstract
Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10(-5)). 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders.

PMID: 25414627 [PubMed - as supplied by publisher]

Protein Interaction Networks Reveal Novel Autism Risk Genes within GWAS Statistical Noise.

November 20, 2014 - 6:02am

Protein Interaction Networks Reveal Novel Autism Risk Genes within GWAS Statistical Noise.

PLoS One. 2014;9(11):e112399

Authors: Correia C, Oliveira G, Vicente AM

Abstract
Genome-wide association studies (GWAS) for Autism Spectrum Disorder (ASD) thus far met limited success in the identification of common risk variants, consistent with the notion that variants with small individual effects cannot be detected individually in single SNP analysis. To further capture disease risk gene information from ASD association studies, we applied a network-based strategy to the Autism Genome Project (AGP) and the Autism Genetics Resource Exchange GWAS datasets, combining family-based association data with Human Protein-Protein interaction (PPI) data. Our analysis showed that autism-associated proteins at higher than conventional levels of significance (P<0.1) directly interact more than random expectation and are involved in a limited number of interconnected biological processes, indicating that they are functionally related. The functionally coherent networks generated by this approach contain ASD-relevant disease biology, as demonstrated by an improved positive predictive value and sensitivity in retrieving known ASD candidate genes relative to the top associated genes from either GWAS, as well as a higher gene overlap between the two ASD datasets. Analysis of the intersection between the networks obtained from the two ASD GWAS and six unrelated disease datasets identified fourteen genes exclusively present in the ASD networks. These are mostly novel genes involved in abnormal nervous system phenotypes in animal models, and in fundamental biological processes previously implicated in ASD, such as axon guidance, cell adhesion or cytoskeleton organization. Overall, our results highlighted novel susceptibility genes previously hidden within GWAS statistical "noise" that warrant further analysis for causal variants.

PMID: 25409314 [PubMed - as supplied by publisher]

Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia.

November 20, 2014 - 6:02am

Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia.

Eur J Hum Genet. 2014 Nov 19;

Authors: Fiorentino A, Sharp SI, McQuillin A

Abstract
The SLC1A2 gene encodes the excitatory amino acid transporter 2 (EAAT2). Glutamate is the major mediator of excitatory neurotransmission and EAAT2 is responsible for clearing the neurotransmitter from the synaptic cleft. Genetic variation in SLC1A2 has been implicated in a range of neurological and neuropsychiatric conditions including schizophrenia (SZ), autism and in core phenotypes of bipolar disorder (BD). The coding and putative regulatory regions of SLC1A2 gene were screened for variants using high resolution melting or sequenced in 1099 or in 32 BD subjects. Thirty-two variants were detected in the SLC1A2 gene. Fifteen potentially etiological variants were selected for genotyping in 1099 BD and 1095 control samples. Five amino acid changing variants were also genotyped in 630 participants suffering from SZ. None of the variants were found to be associated with BD or SZ or with the two diseases combined. However, two recurrent missense variants (rs145827578:G>A, p.(G6S); rs199599866:G>A, p.(R31Q)) and one recurrent 5'-untranslated region (UTR) variant (ss825678885:G>T) were detected in cases only. Combined analysis of the recurrent-case-only missense variants and of the case-only missense and 5'-UTR variants showed nominal evidence for association with the combined diseases (Fisher's P=0.019 and 0.0076). These findings are exploratory in nature and await replication in larger cohorts, however, they provide intriguing evidence that potentially functional rare variants in the SLC1A2 gene may confer susceptibility to psychotic disorders.European Journal of Human Genetics advance online publication, 19 November 2014; doi:10.1038/ejhg.2014.261.

PMID: 25406999 [PubMed - as supplied by publisher]

What causes internalising traits and autistic traits to co-occur in adolescence? A community-based twin study.

November 19, 2014 - 11:46am
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What causes internalising traits and autistic traits to co-occur in adolescence? A community-based twin study.

J Abnorm Child Psychol. 2014 May;42(4):601-10

Authors: Scherff A, Taylor M, Eley TC, Happé F, Charman T, Ronald A

Abstract
Autism shows a high degree of comorbidity with anxiety disorders. Adolescence is a time of increased stress and vulnerability to internalising problems. This study addresses for the first time the degree of genetic and environmental overlap between autistic traits (total measure and subscales) and internalising traits in a community-based adolescent twin sample. Parents of 12-14-year-old twins (N = 3,232 pairs; 3,460 males, 3,004 females) reported on the twins' internalising and autistic traits. Autistic trait subscales were created using principal component analysis. Bivariate twin model-fitting was conducted. Autistic and internalising traits correlated moderately (r = 0.30). Genetic influences on individual traits were substantial but genetic overlap between traits was moderate (genetic correlation: males = 0.30, females = 0.12). Shared environmental influences were low for internalising traits and moderate for autistic traits, and showed considerable overlap (shared environmental correlation: males = 0.53, females = 1). Nonshared environmental influences were moderate for internalising traits and low for autistic traits and showed low overlap. A multiple component solution was found for autistic traits and of the derived subscales, autistic-like 'Social Unease' showed the most phenotypic and genetic overlap with internalising traits.

PMID: 23975079 [PubMed - indexed for MEDLINE]

Brief report: MECP2 mutations in people without Rett syndrome.

November 19, 2014 - 11:46am
Related Articles

Brief report: MECP2 mutations in people without Rett syndrome.

J Autism Dev Disord. 2014 Mar;44(3):703-11

Authors: Suter B, Treadwell-Deering D, Zoghbi HY, Glaze DG, Neul JL

Abstract
Mutations in Methyl-CpG-Binding protein 2 (MECP2) are commonly associated with the neurodevelopmental disorder Rett syndrome (RTT). However, some people with RTT do not have mutations in MECP2, and interestingly there have been people identified with MECP2 mutations that do not have the clinical features of RTT. In this report we present four people with neurodevelopmental abnormalities and clear RTT-disease causing MECP2 mutation but lacking the characteristic clinical features of RTT. One patient's symptoms suggest an extension of the known spectrum of MECP2 associated phenotypes to include global developmental delay with obsessive compulsive disorder and attention deficit hyperactivity disorder. These results reemphasize that RTT should remain a clinical diagnosis, based on the recent consensus criteria.

PMID: 23921973 [PubMed - indexed for MEDLINE]

Shorter telomere length in peripheral blood leukocytes is associated with childhood autism.

November 18, 2014 - 8:22am

Shorter telomere length in peripheral blood leukocytes is associated with childhood autism.

Sci Rep. 2014;4:7073

Authors: Li Z, Tang J, Li H, Chen S, He Y, Liao Y, Wei Z, Wan G, Xiang X, Xia K, Chen X

Abstract
Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Epidemiologic studies have shown that the abnormal telomere length in leukocytes is associated with some mental disorders and age-related diseases. However, the association between leukocyte telomere length and autism has not been investigated. Here we investigated the possible association between relative telomere length (RTL) in peripheral blood leukocytes and childhood autism by using an established real-time polymerase chain reaction method. We observed significantly shorter RTL in patients with childhood autism than in controls (p = 0.006). Individuals with shorter RTL had a significantly increased presence of childhood autism compared with those who had long RTL. In patients, we found that family training interventions have a significant effect on telomere length (P = 0.012), but no correlations between RTL and clinical features (paternal age, maternal age, age of onset, illness of duration, CARS score and ABC score) were observed in this study. These results provided the first evidence that shorter leukocytes telomere length is significantly associated with childhood autism. The molecular mechanism underlying telomere length may be implicated in the development of autism.

PMID: 25399515 [PubMed - in process]

Integrating the roles of long and small non-coding RNA in brain function and disease.

November 18, 2014 - 8:22am
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Integrating the roles of long and small non-coding RNA in brain function and disease.

Mol Psychiatry. 2014 Apr;19(4):410-6

Authors: Barry G

Abstract
Regulatory RNA is emerging as the major architect of cognitive evolution and innovation in the mammalian brain. While the protein machinery has remained largely constant throughout animal evolution, the non protein-coding transcriptome has expanded considerably to provide essential and widespread cellular regulation, partly through directing generic protein function. Both long (long non-coding RNA) and small non-coding RNAs (for example, microRNA) have been demonstrated to be essential for brain development and higher cognitive abilities, and to be involved in psychiatric disease. Long non-coding RNAs, highly expressed in the brain and expanded in mammalian genomes, provide tissue- and activity-specific epigenetic and transcriptional regulation, partly through functional control of evolutionary conserved effector small RNA activity. However, increased cognitive sophistication has likely introduced concomitant psychiatric vulnerabilities, predisposing to conditions such as autism and schizophrenia, and cooperation between regulatory and effector RNAs may underlie neural complexity and concomitant fragility in the human brain.

PMID: 24468823 [PubMed - indexed for MEDLINE]

Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway.

November 18, 2014 - 8:22am
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Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway.

Mol Psychiatry. 2014 Apr;19(4):417-26

Authors: Iafrati J, Orejarena MJ, Lassalle O, Bouamrane L, Gonzalez-Campo C, Chavis P

Abstract
Defective brain extracellular matrix (ECM) is a factor of vulnerability in various psychiatric diseases such as schizophrenia, depression and autism. The glycoprotein reelin is an essential building block of the brain ECM that modulates neuronal development and participates to the functions of adult central synapses. The reelin gene (RELN) is a strong candidate in psychiatric diseases of early onset, but its synaptic and behavioral functions in juvenile brain circuits remain unresolved. Here, we found that in juvenile reelin-haploinsufficient heterozygous reeler mice (HRM), abnormal fear memory erasure is concomitant to reduced dendritic spine density and anomalous long-term potentiation in the prefrontal cortex. In juvenile HRM, a single in vivo injection with ketamine or Ro25-6981 to inhibit GluN2B-N-methyl-D-aspartate receptors (NMDARs) restored normal spine density, synaptic plasticity and converted fear memory to an erasure-resilient state typical of adult rodents. The functional and behavioral rescue by ketamine was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin pathway. Finally, we show that fear memory erasure persists until adolescence in HRM and that a single exposure to ketamine during the juvenile period reinstates normal fear memory in adolescent mice. Our results show that reelin is essential for successful structural, functional and behavioral development of juvenile prefrontal circuits and that this developmental period provides a critical window for therapeutic rehabilitation with GluN2B-NMDAR antagonists.

PMID: 23752244 [PubMed - indexed for MEDLINE]

Factor structure of autistic traits in children with ADHD.

November 18, 2014 - 8:22am
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Factor structure of autistic traits in children with ADHD.

J Autism Dev Disord. 2014 Jan;44(1):204-15

Authors: Martin J, Hamshere ML, O'Donovan MC, Rutter M, Thapar A

Abstract
Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur. Factor analyses of ASD traits in children with and without ASD indicate the presence of social and restrictive-repetitive behaviour (RRB) factors. This study used exploratory factor analyses to determine the structure of ASD traits (assessed using the Social Communication Questionnaire) in children with ADHD. Distinct factors were observed for 'social' and 'rigidity' traits, corresponding to previous factor analyses in clinical ASD and population samples. This indicates that the split between social-communicative and RRB dimensions is unaffected by ADHD in children. Moreover, the study also finds that there is some overlap across hyperactive-impulsive symptoms and RRB traits in children with ADHD, which merits further investigation.

PMID: 23748436 [PubMed - indexed for MEDLINE]

Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits.

November 18, 2014 - 8:22am
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Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits.

Mol Psychiatry. 2014 Apr;19(4):495-503

Authors: Wong CC, Meaburn EL, Ronald A, Price TS, Jeffries AR, Schalkwyk LC, Plomin R, Mill J

Abstract
Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

PMID: 23608919 [PubMed - indexed for MEDLINE]

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]

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