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Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain.

December 18, 2014 - 8:31am
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Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain.

J Biol Chem. 2014 Oct 3;289(40):27585-603

Authors: Reissner C, Stahn J, Breuer D, Klose M, Pohlentz G, Mormann M, Missler M

Abstract
α-Neurexins (α-Nrxn) are mostly presynaptic cell surface molecules essential for neurotransmission that are linked to neuro-developmental disorders as autism or schizophrenia. Several interaction partners of α-Nrxn are identified that depend on alternative splicing, including neuroligins (Nlgn) and dystroglycan (αDAG). The trans-synaptic complex with Nlgn1 was extensively characterized and shown to partially mediate α-Nrxn function. However, the interactions of α-Nrxn with αDAG, neurexophilins (Nxph1) and Nlgn2, ligands that occur specifically at inhibitory synapses, are incompletely understood. Using site-directed mutagenesis, we demonstrate the exact binding epitopes of αDAG and Nxph1 on Nrxn1α and show that their binding is mutually exclusive. Identification of an unusual cysteine bridge pattern and complex type glycans in Nxph1 ensure binding to the second laminin/neurexin/sex hormone binding (LNS2) domain of Nrxn1α, but this association does not interfere with Nlgn binding at LNS6. αDAG, in contrast, interacts with both LNS2 and LNS6 domains without inserts in splice sites SS#2 or SS#4 mostly via LARGE (like-acetylglucosaminyltransferase)-dependent glycans attached to the mucin region. Unexpectedly, binding of αDAG at LNS2 prevents interaction of Nlgn at LNS6 with or without splice insert in SS#4, presumably by sterically hindering each other in the u-form conformation of α-Nrxn. Thus, expression of αDAG and Nxph1 together with alternative splicing in Nrxn1α may prevent or facilitate formation of distinct trans-synaptic Nrxn·Nlgn complexes, revealing an unanticipated way to contribute to the identity of synaptic subpopulations.

PMID: 25157101 [PubMed - indexed for MEDLINE]

Parental social responsiveness and risk of autism spectrum disorder in offspring.

December 18, 2014 - 8:31am
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Parental social responsiveness and risk of autism spectrum disorder in offspring.

JAMA Psychiatry. 2014 Aug;71(8):936-42

Authors: Lyall K, Constantino JN, Weisskopf MG, Roberts AL, Ascherio A, Santangelo SL

Abstract
IMPORTANCE: Although autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of subclinical autistic traits in nonclinical samples are poorly understood.
OBJECTIVE: To examine the familiality of Social Responsiveness Scale (SRS) scores of individuals with and without ASD.
DESIGN, SETTING, AND PARTICIPANTS: We performed a nested case-control study (pilot study: July 1, 2007, through June 30, 2009; full-scale study: September 15, 2008, through September 14, 2012) within a population-based longitudinal cohort. Participants were drawn from the Nurses' Health Study II, a cohort of 116,430 female nurses recruited in 1989. Case participants were index children with reported ASD; control participants were frequency matched by year of birth of case participants among those not reporting ASD. Of 3161 eligible participants, 2144 nurses (67.8%) returned SRS forms for a child and at least 1 parent and were included in these analyses.
EXPOSURE: The SRS scores, as reported by nurse mothers and their spouses, were examined in association with risk of ASD using crude and adjusted logistic regression analyses. The SRS scores of the children were examined in association with SRS scores of the parents using crude and adjusted linear regression analyses stratified by case status.
MAIN OUTCOMES AND MEASURES: Autism spectrum disorder, assessed by maternal report, validated in a subgroup with the Autism Diagnostic Interview-Revised.
RESULTS: A total of 1649 individuals were included in these analyses, including 256 ASD case participants, 1393 control participants, 1233 mothers, and 1614 fathers. Risk of ASD was increased by 85.0% among children whose parents had concordantly elevated SRS scores (odds ratio [OR], 1.85; 95% CI, 1.08-3.16) and by 52.0% when the score of either parent was elevated (OR, 1.52; 95% CI, 1.11-2.06). Elevated scores of the father significantly increased the risk of ASD in the child (OR, 1.94; 95% CI, 1.38-2.71), but no association was seen with elevated scores of the mother. Elevated parent scores significantly increased child scores in controls, corresponding to an increase in 23 points (P < .001).
CONCLUSIONS AND RELEVANCE: These findings support the role of additive genetic influences in concentrating inherited ASD susceptibility in successive generations and the potential role of preferential mating, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits.

PMID: 25100167 [PubMed - indexed for MEDLINE]

Evidence of reproductive stoppage in families with autism spectrum disorder: a large, population-based cohort study.

December 18, 2014 - 8:31am
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Evidence of reproductive stoppage in families with autism spectrum disorder: a large, population-based cohort study.

JAMA Psychiatry. 2014 Aug;71(8):943-51

Authors: Hoffmann TJ, Windham GC, Anderson M, Croen LA, Grether JK, Risch N

Abstract
IMPORTANCE: Few studies have examined the curtailment of reproduction (ie, stoppage) after the diagnosis of a child with autism spectrum disorder (ASD).
OBJECTIVE: To examine stoppage in a large, population-based cohort of families in which a child has received a diagnosis of ASD.
DESIGN, SETTING, AND PARTICIPANTS: Individuals with ASD born from January 1, 1990, through December 31, 2003, were identified in the California Department of Developmental Services records, which were then linked to state birth certificates to identify full sibs and half-sibs and to obtain information on birth order and demographics. A total of 19,710 case families in which the first birth occurred within the study period was identified. These families included 39,361 individuals (sibs and half-sibs). Control individuals were randomly sampled from birth certificates and matched 2:1 to cases by sex, birth year, and maternal age, self-reported race/ethnicity, and county of birth after removal of children receiving services from the California Department of Developmental Services. Using similar linkage methods as for case families, 36,215 pure control families (including 75,724 total individuals) were identified that had no individuals with an ASD diagnosis.
EXPOSURES: History of affected children.
MAIN OUTCOMES AND MEASURES: Stoppage was investigated by comparing the reproductive behaviors of parents after the birth of a child with ASD vs an unaffected child using a survival analysis framework for time to next birth and adjusting for demographic variables.
RESULTS: For the first few years after the birth of a child with ASD, the parents' reproductive behavior was similar to that of control parents. However, birth rates differed in subsequent years; overall, families whose first child had ASD had a second child at a rate of 0.668 (95% CI, 0.635-0.701) that of control families, adjusted for birth year, birth weight, maternal age, and self-reported maternal race/ethnicity. Results were similar when a later-born child was the first affected child in the family. Reproductive curtailment was slightly stronger among women who changed partners (relative rate for second-born children, 0.553 [95% CI, 0.498-0.614]).
CONCLUSIONS AND RELEVANCE: These results provide the first quantitative assessment and convincing statistical evidence of reproductive stoppage related to ASD. These findings have implications for recurrence risk estimation and genetic counseling.

PMID: 24942798 [PubMed - indexed for MEDLINE]

Disrupted brain thyroid hormone homeostasis and altered thyroid hormone-dependent brain gene expression in autism spectrum disorders.

December 17, 2014 - 8:00am
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Disrupted brain thyroid hormone homeostasis and altered thyroid hormone-dependent brain gene expression in autism spectrum disorders.

J Physiol Pharmacol. 2014 Apr;65(2):257-72

Authors: Khan A, Harney JW, Zavacki AM, Sajdel-Sulkowska EM

Abstract
The present study examined human postmortem brains for changes consistent with the hypothesis of local brain TH deficiency in autism spectrum disorders (ASD). Brain levels of oxidative stress marker - 3-nitrotyrosine (3-NT), iodothyronine deiodinase type 2(D2) and type 3 (D3), 3',3,5-triiodothyronine (T3) content, mercury content and gene expression levels were analyzed and compared in the several regions of postmortem brains derived from both male and female control and ASD cases, age 4-16 years. We report that some parameters measured, such as D2 are subject to rapid postmortem inactivation, while others that were analyzed showed both brain region- and sex-dependent changes. Levels of 3-NT were overall increased, T3 was decreased in the cortical regions of ASD brains, while mercury levels measured only in the extracortical regions were not different. The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism.

PMID: 24781735 [PubMed - indexed for MEDLINE]

Mice over-expressing BDNF in forebrain neurons develop an altered behavioral phenotype with age.

December 17, 2014 - 8:00am
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Mice over-expressing BDNF in forebrain neurons develop an altered behavioral phenotype with age.

Behav Brain Res. 2014 Jul 15;268:222-8

Authors: Weidner KL, Buenaventura DF, Chadman KK

Abstract
Evidence from clinical studies suggests that abnormal activity of brain derived neurotrophic factor (BDNF) contributes to the pathogenesis of autism spectrum disorders (ASDs). A genetically modified line of mice over-expressing a BDNF transgene in forebrain neurons was used to investigate if this mutation leads to changes in behavior consistent with ASD. The mice used in these experiments were behaviorally tested past 5 months of age when spontaneous seizures were evident. These seizures were not observed in age-matched wildtype (WT) mice or younger mice from this transgenic line. The BDNF mice in these experiments weighed less than their WT littermates. The BDNF transgenic (BDNF-tg) mice demonstrated similar levels of sociability in the social approach test. Conversely, the BDNF-tg mice demonstrated less obsessive compulsive-like behavior in the marble burying test, less anxiety-like behavior in the elevated plus maze test, and less depressive-like behavior in the forced swim test. Changes in behavior were found in these older mice that have not been observed in younger mice from this transgenic line, which may be due to the development of seizures as the mice age. These mice do not have an ASD phenotype but may be useful to study adult onset epilepsy.

PMID: 24768643 [PubMed - indexed for MEDLINE]

Increased BDNF expression in fetal brain in the valproic acid model of autism.

December 17, 2014 - 8:00am
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Increased BDNF expression in fetal brain in the valproic acid model of autism.

Mol Cell Neurosci. 2014 Mar;59:57-62

Authors: Almeida LE, Roby CD, Krueger BK

Abstract
Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5-6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low-affinity neurotrophin receptor, p75(NTR), doubled. Of the nine 5'-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development.

PMID: 24480134 [PubMed - indexed for MEDLINE]

MeCP2 is required for activity-dependent refinement of olfactory circuits.

December 17, 2014 - 8:00am
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MeCP2 is required for activity-dependent refinement of olfactory circuits.

Mol Cell Neurosci. 2014 Mar;59:63-75

Authors: Degano AL, Park MJ, Penati J, Li Q, Ronnett GV

Abstract
Methyl CpG binding protein 2 (MeCP2) is a structural chromosomal protein involved in the regulation of gene expression. Alterations in the levels of MeCP2 have been related to neurodevelopmental disorders. Studies in mouse models of MeCP2 deficiency have demonstrated that this protein is important for neuronal maturation, neurite complexity, synaptogenesis, and synaptic plasticity. However, the mechanisms by which MeCP2 dysfunction leads to neurodevelopmental defects, and the role of activity, remain unclear, as most studies examine the adult nervous system, which may obfuscate the primary consequences of MeCP2 mutation. We hypothesize that MeCP2 plays a role during the formation and activity-driven maturation of neural circuits at early postnatal stages. To test this hypothesis, we use the olfactory system as a neurodevelopmental model. This system undergoes postnatal neurogenesis; axons from olfactory neurons form highly stereotyped projections to higher-order neurons, facilitating the detection of possible defects in the establishment of connectivity. In vivo olfactory stimulation paradigms were used to produce physiological synaptic activity in gene-targeted mice in which specific olfactory circuits are visualized. Our results reveal defective postnatal refinement of olfactory circuits in Mecp2 knock out (KO) mice after sensory (odorant) stimulation. This failure in refinement was associated with deficits in the normal responses to odorants, including brain-derived neurotrophic factor (BDNF) production, as well as changes in adhesion molecules known to regulate axonal convergence. The defective refinement observed in Mecp2 KO mice was prevented by daily treatment with ampakine beginning after the first postnatal week. These observations indicate that increasing synaptic activity at early postnatal stage might circumvent the detrimental effect of MeCP2 deficiency on circuitry maturation. The present results provide in vivo evidence in real time for the role of MeCP2 in activity-dependent maturation of olfactory circuitry, with implications for understanding the mechanism of MeCP2 mutations in the development of neural connectivity.

PMID: 24472844 [PubMed - indexed for MEDLINE]

De novo single exon deletion of AUTS2 in a patient with speech and language disorder: a review of disrupted AUTS2 and further evidence for its role in neurodevelopmental disorders.

December 17, 2014 - 8:00am
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De novo single exon deletion of AUTS2 in a patient with speech and language disorder: a review of disrupted AUTS2 and further evidence for its role in neurodevelopmental disorders.

Am J Med Genet A. 2014 Apr;164A(4):958-65

Authors: Amarillo IE, Li WL, Li X, Vilain E, Kantarci S

Abstract
The autism susceptibility candidate 2 (AUTS2) gene is suggested to play a critical role in early brain development, and its association with intellectual disability (ID), autism spectrum disorders, and other neurodevelopmental disorders (NDDs) has recently gained more attention. Genomic rearrangements and copy number variations (CNVs) involving AUTS2 have been implicated in a range of NDDs with or without congenital malformations and dysmorphic features. Here we report a 62 kb de novo deletion encompassing exon 6 of AUTS2 detected by chromosomal microarray analysis (CMA) in a 4.5 year-old female patient with severe speech and language disorder, history of tonic-clonic movements, and pes planus with eversion of the feet. This is one of the smallest de novo intragenic deletions of AUTS2 described in patients with NDDs. We reviewed previously reported small pathogenic CNVs (<300 kb) in 19 cases, and correlated their specific locations within AUTS2 as well as presence of enhancers, regulatory elements, and CpG islands with the clinical findings of these cases and our patient. Our report provides additional insight into the clinical spectrum of AUTS2 disruptions.

PMID: 24459036 [PubMed - indexed for MEDLINE]

MECP2 duplication: possible cause of severe phenotype in females.

December 17, 2014 - 8:00am
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MECP2 duplication: possible cause of severe phenotype in females.

Am J Med Genet A. 2014 Apr;164A(4):1029-34

Authors: Scott Schwoerer J, Laffin J, Haun J, Raca G, Friez MJ, Giampietro PF

Abstract
MECP2 duplication syndrome, originally described in 2005, is an X-linked neurodevelopmental disorder comprising infantile hypotonia, severe to profound intellectual disability, autism or autistic-like features, spasticity, along with a variety of additional features that are not always clinically apparent. The syndrome is due to a duplication (or triplication) of the gene methyl CpG binding protein 2 (MECP2). To date, the disorder has been described almost exclusively in males. Female carriers of the duplication are thought to have no or mild phenotypic features. Recently, a phenotype for females began emerging. We describe a family with ∼290 kb duplication of Xq28 region that includes the MECP2 gene where the proposita and affected family members are female. Twin sisters, presumed identical, presented early with developmental delay, and seizures. Evaluation of the proposita at 25 years of age included microarray comparative genomic hybridization (aCGH) which revealed the MECP2 gene duplication. The same duplication was found in the proposita's sister, who is more severely affected, and the proband's mother who has mild intellectual disability and depression. X-chromosome inactivation studies showed significant skewing in the mother, but was uninformative in the twin sisters. We propose that the MECP2 duplication caused for the phenotype of the proband and her sister. These findings support evidence for varied severity in some females with MECP2 duplications.

PMID: 24458799 [PubMed - indexed for MEDLINE]

Behavioral profile in RASopathies.

December 17, 2014 - 8:00am
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Behavioral profile in RASopathies.

Am J Med Genet A. 2014 Apr;164A(4):934-42

Authors: Alfieri P, Piccini G, Caciolo C, Perrino F, Gambardella ML, Mallardi M, Cesarini L, Leoni C, Leone D, Fossati C, Selicorni A, Digilio MC, Tartaglia M, Mercuri E, Zampino G, Vicari S

Abstract
Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.

PMID: 24458522 [PubMed - indexed for MEDLINE]

Duplication at Xq13.3-q21.1 with syndromic intellectual disability, a probable role for the ATRX gene.

December 17, 2014 - 8:00am
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Duplication at Xq13.3-q21.1 with syndromic intellectual disability, a probable role for the ATRX gene.

Am J Med Genet A. 2014 Apr;164A(4):918-23

Authors: Martínez F, Roselló M, Mayo S, Monfort S, Oltra S, Orellana C

Abstract
Here we report on two unrelated male patients with syndromic intellectual disability (ID) due to duplication at Xq13.3-q21.1, a region of about 6 Mb and 25 genes. Among these, the most outstanding is ATRX, the causative gene of X-linked alpha-thalassemia/mental retardation. ATRX belongs to the growing list of genes implied in chromatin remodeling causing ID. Many these genes, such as MECP2, are dose-sensitive so that not only deletions and point mutations, but also duplications cause ID. Both patients have severe ID, absent expressive speech, early hypotonia, behavior problems (hyperactivity, repetitive self-stimulatory behavior), postnatal growth deficiency, microcephaly, micrognathia, cryptorchidism, low-set, posteriorly angulated ears, and downslanting palpebral fissures. These findings are also usually present among patients with loss-of-function mutations of the ATRX gene. Completely skewed X inactivation was observed in the only informative carrier mother, a constant finding among female carriers of inactivating point mutations of this gene. Participation of other duplicated genes cannot be excluded; nevertheless we propose that the increased dosage of ATRX is the major pathogenic mechanism of this X-linked disorder, a syndrome reminiscent of MECP2 duplication.

PMID: 24458433 [PubMed - indexed for MEDLINE]

Sexual dimorphic effect in the genetic association of monoamine oxidase A (MAOA) markers with autism spectrum disorder.

December 17, 2014 - 8:00am
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Sexual dimorphic effect in the genetic association of monoamine oxidase A (MAOA) markers with autism spectrum disorder.

Prog Neuropsychopharmacol Biol Psychiatry. 2014 Apr 3;50:11-20

Authors: Verma D, Chakraborti B, Karmakar A, Bandyopadhyay T, Singh AS, Sinha S, Chatterjee A, Ghosh S, Mohanakumar KP, Mukhopadhyay K, Rajamma U

Abstract
Autism spectrum disorders are heritable and behaviorally-defined neurodevelopmental disorders having skewed sex ratio. Serotonin as modulator of behavior and implication of serotonergic dysfunction in ASD etiology corroborates that serotonergic system genes are potential candidates for autism susceptibility. In the current study X-chromosomal gene, MAOA responsible for degradation of serotonin is investigated for possible association with ASD using population-based approach. Study covers analysis of 8 markers in 421 subjects including cases and ethnically-matched controls from West Bengal. MAOA marker, rs6323 and various haplotypes formed between the markers show significant association with the disorder. Stratification on the basis of sex reveals significant genetic effect of rs6323 with low activity T allele posing higher risk in males, but not in females. Haplotypic association results also show differential effect both in males and females. Contrasting linkage disequilibrium pattern between pair of markers involving rs6323 in male cases and controls further supports the sex-bias in genetic association. Bioinformatic analysis shows presence of Y-encoded SRY transcription factor binding sites in the neighborhood of rs1137070. C allele of rs1137070 causes deletion of GATA-2 binding site and GATA-2 is known to interact with SRY. This is the first study highlighting male-specific effect of rs6323 marker and its haplotypes in ASD etiology and it suggests sexual dimorphic effect of MAOA in this disorder. Overall results of this study identify MAOA as a possible ASD susceptibility locus and the differential genetic effect in males and females might contribute to the sex ratio differences and molecular pathology of the disorder.

PMID: 24291416 [PubMed - indexed for MEDLINE]

Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders.

December 17, 2014 - 8:00am
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Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders.

Neuropharmacology. 2014 May;80:18-27

Authors: Vogel-Ciernia A, Wood MA

Abstract
Long-term memory formation requires the coordinated regulation of gene expression. Until recently nucleosome remodeling, one of the major epigenetic mechanisms for controlling gene expression, had been largely unexplored in the field of neuroscience. Nucleosome remodeling is carried out by chromatin remodeling complexes (CRCs) that interact with DNA and histones to physically alter chromatin structure and ultimately regulate gene expression. Human exome sequencing and gene wide association studies have linked mutations in CRC subunits to intellectual disability disorders, autism spectrum disorder and schizophrenia. However, how mutations in CRC subunits were related to human cognitive disorders was unknown. There appears to be both developmental and adult specific roles for the neuron specific CRC nBAF (neuronal Brg1/hBrm Associated Factor). nBAF regulates gene expression required for dendritic arborization during development, and in the adult, contributes to long-term potentiation, a form of synaptic plasticity, and long-term memory. We propose that the nBAF complex is a novel epigenetic mechanism for regulating transcription required for long-lasting forms of synaptic plasticity and memory processes and that impaired nBAF function may result in human cognitive disorders.

PMID: 24140580 [PubMed - indexed for MEDLINE]

[Oxidative stress, rRNA genes, and antioxidant enzymes in pathogenesis of schizophrenia and autism: modeling and clinical advices].

December 17, 2014 - 8:00am
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[Oxidative stress, rRNA genes, and antioxidant enzymes in pathogenesis of schizophrenia and autism: modeling and clinical advices].

Zh Obshch Biol. 2013 Sep-Oct;74(5):340-53

Authors: Porokhovnik LN, Pasekov VP, Egolina NA, Tsvetkova TG, Kosiakova NV, Gorbachevskaia NL, Sukhotina NK, Kozlovskaia GV, Sorokin AB, Korovina NIu, Liapunova NA

Abstract
Ribosomal genes (RG), or genes for rRNA, are represented by multiple tandem repeats in eukaryotic genomes, and just a part of them is transcriptionally active. The quantity of active copies is a stable genome feature which determines the cell's capability for rapid synthesis of proteins, necessary to cope with stress conditions. Low number of active RG copies leads to reduced stress resistance and elevated risk of multifactorial disorders (MFD). Oxidative stress (OS) in the brain cells is believed to be involved in the pathogenesis of infantile autism (IA) and schizophrenia, i.e., MFDs with a manifested genetic predisposition. With autism, OS markers are found almost in every research, whilst with schizophrenia, the OS data are contradictory. Earlier, in a sample of patients with schizophrenia, we have found significantly higher quantity of active RG copies than at the average in healthy population. Here we have estimated the number of active RG copies in a sample of patients with IA (n = 51) and revealed significantly lower mean value than in healthy population. A novel mathematical model of the dynamic pattern of OS has been proposed. The model is realized as an ordinary differential equation system, supposing induction of antioxidant protection enzymes being mediated by reactive oxygen species (ROS), with the subsequent decrease of ROS content in a cell. The rate of synthesis of antioxidant protection enzymes is limited by the ribosome synthesis rate which depends on the number of active RG copies. Analysis of the model showed that the system always approaches a single stable equilibrium point along a damped oscillation trajectory, which in some degree resembles the dynamics of 'predator-prey' interaction in Lotka-Volterra model. The stationary ROS level inversely depends on the number of active RG copies. Our study explains the inconsistency of clinical data of OS in schizophrenia and suggests a novel criterion for discriminative cytogenetic diagnostics of schizophrenia and IA, as well as allows to assume that antioxidant therapy should be effective only for children with low number of active RG copies.

PMID: 25438566 [PubMed - indexed for MEDLINE]

Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients.

December 15, 2014 - 3:19pm
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Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients.

Parkinsonism Relat Disord. 2014 Mar;20(3):332-6

Authors: Verhoeven WM, Egger JI, Koolen DA, Yntema H, Olgiati S, Breedveld GJ, Bonifati V, van de Warrenburg BP

Abstract
Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare neuropsychiatric syndromes characterized by iron accumulation in the basal ganglia. The pantothenate kinase-associated neurodegeneration (PKAN) was the first NBIA form to be genetically identified almost 15 years ago. Nowadays, eight types can be genetically distinguished. More recently, a novel NBIA was delineated and termed Static Encephalopathy of childhood with Neurodegeneration in Adulthood (SENDA), characterized by early intellectual disability followed by delayed progressive motor and cognitive deterioration with an onset in the second to third decade. Very recently, mutations in the WD repeat-containing protein 45 (WDR45) gene located on Xp11.23 were shown to be the causal factor. The protein encoded by WDR45 propels protein interaction important for autophagy. This form was therefore retermed Beta-propeller Protein Associated Neurodegeneration (BPAN). Here, the first three Dutch patients with genetically proven BPAN are comprehensively described with respect to course and neurological as well as neuropsychiatric phenotypes. All three showed a characteristic delayed progression of neurological symptoms with parkinsonism and prominent dystonia. Treatment with levodopa/carbidopa had limited effects only. Neuropsychiatric symptoms within the autistic and affective spectrum were present in the early phase of the disease. The specific course and prognosis should implicate restrained psychopharmacological interventions. The clinical picture and imaging hallmarks are often highly suggestive and should lead to suspect this specific disorder. However, the identification of a WDR45 mutation is needed for a definite diagnosis of BPAN.

PMID: 24368176 [PubMed - indexed for MEDLINE]

Reviewing the ketamine model for schizophrenia.

December 15, 2014 - 3:19pm
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Reviewing the ketamine model for schizophrenia.

J Psychopharmacol. 2014 Apr;28(4):287-302

Authors: Frohlich J, Van Horn JD

Abstract
The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory γ-aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia.

PMID: 24257811 [PubMed - indexed for MEDLINE]

Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory.

December 15, 2014 - 3:19pm
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Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory.

Hum Mol Genet. 2014 Apr 1;23(7):1771-82

Authors: Cao L, Molina J, Abad C, Carmona-Mora P, Cárdenas Oyarzo A, Young JI, Walz K

Abstract
Potocki-Lupski syndrome (PTLS) is a genomic disorder associated with an ∼3 Mb duplication in 17p11.2. Clinical features include leanness, intellectual disability, autistic features and developmental deficits. RAI1 gene dosage is associated with the PTLS phenotypes. To understand where and when Rai1 overexpression is detrimental, we generated a mouse that over-expresses Rai1 conditionally in forebrain neurons (I-Rai1). Phenotypic characterization of I-Rai1 mice showed significant underweight, hyperactivity and impaired learning and memory ability compared with wild-type littermates. Doxycycline administration can turn off the transgene expression allowing the restoration of Rai1 normal expression levels. When the transgene was turned off from conception to 3 months of age, no phenotypic differences were observed between I-Rai1 and their wild-type littermates. Surprisingly, we found that turning off the transgene expression before the onset of the phenotypes (1-3 months) or after the onset of the phenotypes (3-5 months) cannot prevent nor reverse the phenotypic outcomes. Our results indicate that Rai1 dosage in forebrain neurons is critical during the development and is related to body weight regulation, activity levels and learning and memory.

PMID: 24218365 [PubMed - indexed for MEDLINE]

Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation.

December 15, 2014 - 3:19pm
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Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation.

Neuropsychopharmacology. 2014 Apr;39(5):1125-34

Authors: Del'Guidice T, Lemay F, Lemasson M, Levasseur-Moreau J, Manta S, Etievant A, Escoffier G, Doré FY, Roman FS, Beaulieu JM

Abstract
Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

PMID: 24196946 [PubMed - indexed for MEDLINE]

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

December 15, 2014 - 3:19pm
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22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

Genet Med. 2014 Apr;16(4):318-28

Authors: Sarasua SM, Dwivedi A, Boccuto L, Chen CF, Sharp JL, Rollins JD, Collins JS, Rogers RC, Phelan K, DuPont BR

Abstract
PURPOSE: Phelan-McDermid syndrome is a developmental disability syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features.
METHODS: We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features.
RESULTS: Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders.
CONCLUSION: This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan-McDermid syndrome. Our statistical approach may be useful in genotype-phenotype analyses for other microdeletion or microduplication syndromes.

PMID: 24136618 [PubMed - indexed for MEDLINE]

Autoantibodies against neuronal progenitors in sera from children with autism.

December 15, 2014 - 3:19pm
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Autoantibodies against neuronal progenitors in sera from children with autism.

Brain Dev. 2014 Apr;36(4):322-9

Authors: Mazur-Kolecka B, Cohen IL, Gonzalez M, Jenkins EC, Kaczmarski W, Brown WT, Flory M, Frackowiak J

Abstract
The pathological role of autoantibodies in development of CNS disorders is a new idea with growing interest among neuroscientists. The involvement of autoimmune response in the pathogenesis of autism spectrum disorders (ASD) has been suggested by the presence of multiple brain-specific autoantibodies in children with ASD and in their mothers. The possibility of the effect of autoimmunity on neurogenesis and postnatal brain plasticity has not been determined. The presence of autoantibodies against human neuronal progenitor cells (NPCs) stimulated for neuronal differentiation in culture was tested in sera from children with autism (n=20) and age-matched controls (n=18) by immunoblotting and immunocytochemistry. Immunoreactivity against multiple NPCs proteins of molecular sizes of approximately 55 kDa, 105 kDa, 150 kDa, and 210 kDa in sera from individuals with autism had a higher incidence and was stronger than in control sera which immunoreacted mainly with a 150 kDa protein. The sera from children with autism immunoreacted the strongest with NPCs expressing neuronal markers Tuj1 and doublecortin, but not astrocyte marker GFAP. The epitopes recognized by antibodies from sera were not human-specific because they detected also NPCs in situ in murine hippocampus. The autoimmune reactions against NPCs suggest an impaired tolerance to neural antigens in autism. These autoantibodies may be symptomatic for autism and furthermore, their presence suggests that autoimmunity may affect postnatal neuronal plasticity particularly after impairment of blood-brain barrier. Future studies will determine the diagnostic value of the presence of autoantibodies in autism and the therapeutic value of prevention of autoimmunity in autism.

PMID: 23838310 [PubMed - indexed for MEDLINE]

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