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A spectral approach integrating functional genomic annotations for coding and noncoding variants.

January 5, 2016 - 7:49am

A spectral approach integrating functional genomic annotations for coding and noncoding variants.

Nat Genet. 2016 Jan 4;

Authors: Ionita-Laza I, McCallum K, Xu B, Buxbaum JD

Abstract
Over the past few years, substantial effort has been put into the functional annotation of variation in human genome sequences. Such annotations can have a critical role in identifying putatively causal variants for a disease or trait among the abundant natural variation that occurs at a locus of interest. The main challenges in using these various annotations include their large numbers and their diversity. Here we develop an unsupervised approach to integrate these different annotations into one measure of functional importance (Eigen) that, unlike most existing methods, is not based on any labeled training data. We show that the resulting meta-score has better discriminatory ability using disease-associated and putatively benign variants from published studies (in both coding and noncoding regions) than the recently proposed CADD score. Across varied scenarios, the Eigen score performs generally better than any single individual annotation, representing a powerful single functional score that can be incorporated in fine-mapping studies.

PMID: 26727659 [PubMed - as supplied by publisher]

The possible link between elevated serum levels of epithelial cell-derived neutrophil-activating peptide-78 (ENA-78/CXCL5) and autoimmunity in autistic children.

January 5, 2016 - 7:49am
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The possible link between elevated serum levels of epithelial cell-derived neutrophil-activating peptide-78 (ENA-78/CXCL5) and autoimmunity in autistic children.

Behav Brain Funct. 2015;11:11

Authors: Mostafa GA, Al-Ayadhi LY

Abstract
BACKGROUND: In autoimmune disorders, the underlying pathogenic mechanism is the formation of antigen-antibody complexes which trigger an inflammatory response by inducing the infiltration of neutrophils. Epithelial cell-derived neutrophil-activating peptide-78 (ENA-78) is a chemokine that recruits and activates neutrophils, thus it could play a pathogenic role in inflammation and autoimmune disorders. Some autistic children have elevated levels of brain specific auto-antibodies. We are the first to evaluate serum expression of ENA-78 and its relation to antineuronal auto-antibodies in autistic children.
METHODS: Serum ENA-78 and antineuronal auto-antibodies were measured by ELISA test in 62 autistic children aged between 4-11 years and 62 health-matched controls.
RESULTS: Serum levels of ENA-78 were significantly higher in autistic children than healthy controls (P < 0.001). Increased serum levels of ENA-78 have been found in 69.35% of autistic patients. In addition, autistic children had significantly higher percent positivity of serum antineuronal auto-antibodies (64.5%) than healthy controls (6.45%), P < 0.001. There was a significant positive association between the positivity of serum antineuronal auto-antibodies and the elevated levels of serum ENA-78 (P < 0.001) in autistic children.
CONCLUSIONS: Serum levels of ENA-78 were elevated in autistic children and they were significantly associated with the increased levels of serum antineuronal auto-antibodies. However, these data should be treated with caution until further research is conducted to determine the pathogenic role of ENA-78 in autism and its relation to brain specific auto-antibodies that have been found in some autistic children. The possible therapeutic role of ENA-78 antagonist in autistic children should be also studied.

PMID: 25871636 [PubMed - indexed for MEDLINE]

Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder.

January 5, 2016 - 7:49am
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Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder.

Int J Mol Sci. 2015;16(4):7627-43

Authors: Mullegama SV, Alaimo JT, Chen L, Elsea SH

Abstract
Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention.

PMID: 25853262 [PubMed - indexed for MEDLINE]

Disease gene prioritization using network and feature.

January 5, 2016 - 7:49am
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Disease gene prioritization using network and feature.

J Comput Biol. 2015 Apr;22(4):313-23

Authors: Xie B, Agam G, Balasubramanian S, Xu J, Gilliam TC, Maltsev N, Börnigen D

Abstract
Identifying high-confidence candidate genes that are causative for disease phenotypes, from the large lists of variations produced by high-throughput genomics, can be both time-consuming and costly. The development of novel computational approaches, utilizing existing biological knowledge for the prioritization of such candidate genes, can improve the efficiency and accuracy of the biomedical data analysis. It can also reduce the cost of such studies by avoiding experimental validations of irrelevant candidates. In this study, we address this challenge by proposing a novel gene prioritization approach that ranks promising candidate genes that are likely to be involved in a disease or phenotype under study. This algorithm is based on the modified conditional random field (CRF) model that simultaneously makes use of both gene annotations and gene interactions, while preserving their original representation. We validated our approach on two independent disease benchmark studies by ranking candidate genes using network and feature information. Our results showed both high area under the curve (AUC) value (0.86), and more importantly high partial AUC (pAUC) value (0.1296), and revealed higher accuracy and precision at the top predictions as compared with other well-performed gene prioritization tools, such as Endeavour (AUC-0.82, pAUC-0.083) and PINTA (AUC-0.76, pAUC-0.066). We were able to detect more target genes (9/18/19/27) on top positions (1/5/10/20) compared to Endeavour (3/11/14/23) and PINTA (6/10/13/18). To demonstrate its usability, we applied our method to a case study for the prediction of molecular mechanisms contributing to intellectual disability and autism. Our approach was able to correctly recover genes related to both disorders and provide suggestions for possible additional candidates based on their rankings and functional annotations.

PMID: 25844670 [PubMed - indexed for MEDLINE]

Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.

January 5, 2016 - 7:49am
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Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.

Eur J Neurosci. 2015 Apr;41(8):1025-35

Authors: Mao W, Watanabe T, Cho S, Frost JL, Truong T, Zhao X, Futai K

Abstract
The Shank genes (SHANK1, 2, 3) encode scaffold proteins highly enriched in postsynaptic densities where they regulate synaptic structure in spiny neurons. Mutations in human Shank genes are linked to autism spectrum disorder and schizophrenia. Shank1 mutant mice exhibit intriguing cognitive phenotypes reminiscent of individuals with autism spectrum disorder. However, the molecular mechanisms leading to the human pathophysiological phenotypes and mouse behaviors have not been elucidated. In this study it is shown that Shank1 protein is highly localized in parvalbumin-expressing (PV+) fast-spiking inhibitory interneurons in the hippocampus. Importantly, a lack of Shank1 in hippocampal CA1 PV+ neurons reduced excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons. Furthermore, it is demonstrated that hippocampal CA1 pyramidal neurons in Shank1 mutant mice exhibit a shift in the excitatory and inhibitory balance (E-I balance), a pathophysiological hallmark of autism spectrum disorder. The mutant mice also exhibit lower expression of gephyrin (a scaffold component of inhibitory synapses), supporting the dysregulation of E-I balance in the hippocampus. These results suggest that Shank1 scaffold in PV+ interneurons regulates excitatory synaptic strength and participates in the maintenance of E-I balance in excitatory neurons.

PMID: 25816842 [PubMed - indexed for MEDLINE]

Single-quantum-dot tracking reveals altered membrane dynamics of an attention-deficit/hyperactivity-disorder-derived dopamine transporter coding variant.

January 5, 2016 - 7:49am
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Single-quantum-dot tracking reveals altered membrane dynamics of an attention-deficit/hyperactivity-disorder-derived dopamine transporter coding variant.

ACS Chem Neurosci. 2015 Apr 15;6(4):526-34

Authors: Kovtun O, Sakrikar D, Tomlinson ID, Chang JC, Arzeta-Ferrer X, Blakely RD, Rosenthal SJ

Abstract
The presynaptic, cocaine- and amphetamine-sensitive dopamine (DA) transporter (DAT, SLC6A3) controls the intensity and duration of synaptic dopamine signals by rapid clearance of DA back into presynaptic nerve terminals. Abnormalities in DAT-mediated DA clearance have been linked to a variety of neuropsychiatric disorders, including addiction, autism, and attention deficit/hyperactivity disorder (ADHD). Membrane trafficking of DAT appears to be an important, albeit incompletely understood, post-translational regulatory mechanism; its dysregulation has been recently proposed as a potential risk determinant of these disorders. In this study, we demonstrate a link between an ADHD-associated DAT mutation (Arg615Cys, R615C) and variation on DAT transporter cell surface dynamics, a combination only previously studied with ensemble biochemical and optical approaches that featured limited spatiotemporal resolution. Here, we utilize high-affinity, DAT-specific antagonist-conjugated quantum dot (QD) probes to establish the dynamic mobility of wild-type and mutant DATs at the plasma membrane of living cells. Single DAT-QD complex trajectory analysis revealed that the DAT 615C variant exhibited increased membrane mobility relative to DAT 615R, with diffusion rates comparable to those observed after lipid raft disruption. This phenomenon was accompanied by a loss of transporter mobilization triggered by amphetamine, a common component of ADHD medications. Together, our data provides the first dynamic imaging of single DAT proteins, providing new insights into the relationship between surface dynamics and trafficking of both wild-type and disease-associated transporters. Our approach should be generalizable to future studies that explore the possibilities of perturbed surface DAT dynamics that may arise as a consequence of genetic alterations, regulatory changes, and drug use that contribute to the etiology or treatment of neuropsychiatric disorders.

PMID: 25747272 [PubMed - indexed for MEDLINE]

Quantitative proteomics analysis of CaMKII phosphorylation and the CaMKII interactome in the mouse forebrain.

January 5, 2016 - 7:49am
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Quantitative proteomics analysis of CaMKII phosphorylation and the CaMKII interactome in the mouse forebrain.

ACS Chem Neurosci. 2015 Apr 15;6(4):615-31

Authors: Baucum AJ, Shonesy BC, Rose KL, Colbran RJ

Abstract
Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) autophosphorylation at Thr286 and Thr305/Thr306 regulates kinase activity and modulates subcellular targeting and is critical for normal synaptic plasticity and learning and memory. Here, a mass spectrometry-based approach was used to identify Ca(2+)-dependent and -independent in vitro autophosphorylation sites in recombinant CaMKIIα and CaMKIIβ. CaMKII holoenzymes were then immunoprecipitated from subcellular fractions of forebrains isolated from either wild-type (WT) mice or mice with a Thr286 to Ala knock-in mutation of CaMKIIα (T286A-KI mice) and analyzed using the same approach in order to characterize in vivo phosphorylation sites in both CaMKII isoforms and identify CaMKII-associated proteins (CaMKAPs). A total of six and seven autophosphorylation sites in CaMKIIα and CaMKIIβ, respectively, were detected in WT mice. Thr286-phosphorylated CaMKIIα and Thr287-phosphorylated CaMKIIβ were selectively enriched in WT Triton-insoluble (synaptic) fractions compared to Triton-soluble (membrane) and cytosolic fractions. In contrast, Thr306-phosphorylated CaMKIIα and Ser315- and Thr320/Thr321-phosphorylated CaMKIIβ were selectively enriched in WT cytosolic fractions. The T286A-KI mutation significantly reduced levels of phosphorylation of CaMKIIα at Ser275 across all subcellular fractions and of cytosolic CaMKIIβ at Ser315 and Thr320/Thr321. Significantly more CaMKAPs coprecipitated with WT CaMKII holoenzymes in the synaptic fraction compared to that in the membrane fraction, with functions including scaffolding, microtubule organization, actin organization, ribosomal function, vesicle trafficking, and others. The T286A-KI mutation altered the interactions of multiple CaMKAPs with CaMKII, including several proteins linked to autism spectrum disorders. These data identify CaMKII isoform phosphorylation sites and a network of synaptic protein interactions that are sensitive to the abrogation of Thr286 autophosphorylation of CaMKIIα, likely contributing to the diverse synaptic and behavioral deficits of T286A-KI mice.

PMID: 25650780 [PubMed - indexed for MEDLINE]

Lack of evidence for genomic instability in autistic children as measured by the cytokinesis-block micronucleus cytome assay.

January 5, 2016 - 7:49am
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Lack of evidence for genomic instability in autistic children as measured by the cytokinesis-block micronucleus cytome assay.

Autism Res. 2015 Feb;8(1):94-104

Authors: Main PA, Thomas P, Angley MT, Young R, Esterman A, King CE, Fenech MF

Abstract
Autism spectrum disorders are a set of neurodevelopmental disorders that are highly hereditable. Increased genomic instability has been observed in other heritable paediatric neurobiological disorders; therefore, the aim of our study was to test the hypothesis that DNA damage is increased in children with autism and that B vitamin status may explain variations in genome integrity between autistic and normal children. We compared 35 children with autism, 27 of their siblings without autism and 25 age- and gender-matched community controls for genomic stability using the cytokinesis-block micronucleus cytome (CBMN-cyt) assay, B vitamins and homocysteine, as well as autism-related behaviours. It was found that there were no differences in CBMN-cyt biomarkers between the three groups. Vitamin B2 was significantly raised in children with autism and their siblings compared with controls (P = 0.027 and P = 0.016 respectively) but there was no difference in other B vitamins or homocysteine. In conclusion, although replication using a larger cohort is needed, it appears unlikely that genomic instability is a feature of the aetiology of autism. We cannot rule out in utero effects or other types of DNA damage not measured by the CBMN-cyt assay.

PMID: 25371234 [PubMed - indexed for MEDLINE]

[The amygdala and its relation to autism, behavioural disorders and other neurodevelopmental disorders].

January 5, 2016 - 7:49am
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[The amygdala and its relation to autism, behavioural disorders and other neurodevelopmental disorders].

Rev Neurol. 2014 Feb 24;58 Suppl 1:S137-48

Authors: Ruggieri VL

Abstract
The amygdala is related with the recognition of the emotional meaning of stimuli, long-term memory, the orientation of social stimuli and the perception of gaze orientation. It plays a fundamental role in the recognition of faces, especially those expressing fear, and makes it possible to comprehend different emotional states, which will facilitate an appropriate social cognition. Dysfunctions of the amygdala have been associated to a number of different neurodevelopmental disorders as well as neurocognitive and behavioural disorders in specific neurogenetic entities. A number of studies focused on the amygdalic complex have allowed researchers to understand many pathophysiological aspects and to formulate new hypotheses regarding their origins. Given that the disorders or conditions in which the role of the amygdala has been evoked are becoming increasingly more extensive, this article refers the reader to those that have aroused the most interest in recent years. Thus, they can be divided into two groups: developmental and behavioural disorders (autism, anxiety disorders, bipolar disorder, alexithymia and anorexia nervosa) and specific neurogenetic entities (fragile X, Rett, Prader-Willi and Williams syndromes), in which structural or dysfunctional alterations have been observed that may be related with their neurocognitive and behavioural symptoms. It is important to remember that the amygdala is a highly connected structure that forms truly functional networks and has been associated to different disorders with varied explanations and includes several different pathophysiological phenomena. Its role must not, therefore, be simplified in a reductionistic manner, but also placed upon a hierarchy of dysfunctions in other areas that interact with it.

PMID: 25252660 [PubMed - indexed for MEDLINE]

Inactivation of the catalytic phosphatase domain of PTPRT/RPTPρ increases social interaction in mice.

January 5, 2016 - 7:49am
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Inactivation of the catalytic phosphatase domain of PTPRT/RPTPρ increases social interaction in mice.

Autism Res. 2015 Feb;8(1):19-28

Authors: Thirtamara Rajamani K, O'Neill B, Han DD, Frostholm A, Rotter A, Gu HH

Abstract
Receptor protein tyrosine phosphatase rho (RPTPρ, gene symbol PTPRT) is a transmembrane protein expressed at high levels in the developing hippocampus, olfactory bulb, cortex, and cerebellum. It has an extracellular domain that interacts with other cell adhesion molecules, and it has two intracellular phosphatase domains, one of which is catalytically active. In a recent genome-wide association study, PTPRT was identified as a potential candidate gene for autism spectrum disorder (ASD) susceptibility. Mutation of a critical aspartate to alanine (D1046A) in the PTPRT catalytic domain inactivates phosphatase function but retains substrate binding. We have generated a knockin mouse line carrying the PTPRT D1046A mutation. The D1046A mutation in homozygous knockin mice did not significantly change locomotor activities or anxiety-related behaviors. In contrast, male homozygous mice had significantly higher social approach scores than wild-type animals. Our results suggest that PTPRT phosphatase function is important in modulating neural pathways involved in mouse social behaviors relevant to the symptoms in human ASD patients.

PMID: 24895325 [PubMed - indexed for MEDLINE]

Developmental Neurotoxicity of Inhaled Ambient Ultrafine Particle Air Pollution: Parallels with Neuropathological and Behavioral Features of Autism and Other Neurodevelopmental Disorders.

January 2, 2016 - 7:45am

Developmental Neurotoxicity of Inhaled Ambient Ultrafine Particle Air Pollution: Parallels with Neuropathological and Behavioral Features of Autism and Other Neurodevelopmental Disorders.

Neurotoxicology. 2015 Dec 22;

Authors: Allen JL, Oberdorster G, Morris-Schafer K, Wong C, Klocke C, Sobolewski M, Conrad K, M MP, Cory-Slechta DA

Abstract
Accumulating evidence from both human and animal studies show that brain is a target of air pollution. Multiple epidemiological studies have now linked components of air pollution to diagnosis of autism spectrum disorder (ASD), a linkage with plausibility based on the shared mechanisms of inflammation. Additional plausibility appears to be provided by findings from our studies in mice of exposures from postnatal day (PND) 4-7 and 10-13 (human 3rd trimester equivalent), to concentrated ambient ultrafine (UFP) particles, considered the most reactive component of air pollution, at levels consistent with high traffic areas of major U.S. cities and thus highly relevant to human exposures. These exposures, occurring during a period of marked neuro- and gliogenesis, unexpectedly produced a pattern of developmental neurotoxicity notably similar to multiple hypothesized mechanistic underpinnings of ASD, including its greater impact in males. UFP exposures induced inflammation/microglial activation, reductions in size of the corpus callosum (CC) and associated hypomyelination, aberrant white matter development and/or structural integrity with ventriculomegaly (VM), elevated glutamate and excitatory/inhibitory imbalance, increased amygdala astrocytic activation, and repetitive and impulsive behaviors. Collectively, these findings suggest the human 3rd trimester equivalent as a period of potential vulnerability to neurodevelopmental toxicity to UFP, particularly in males, and point to the possibility that UFP air pollution exposure during periods of rapid neuro- and gliogenesis may be a risk factor not only for ASD, but also for other neurodevelopmental disorders that share features with ASD, such as schizophrenia, attention deficit disorder, and periventricular leukomalacia.

PMID: 26721665 [PubMed - as supplied by publisher]

Shooting a moving target. Researching autism genes: an interview study with professionals.

January 2, 2016 - 7:45am

Shooting a moving target. Researching autism genes: an interview study with professionals.

Eur J Med Genet. 2015 Dec 22;

Authors: Hens K, Peeters H, Dierickx K

Abstract
BACKGROUND: Given the wide variety of the phenotype, the uncertain genetic origins and the discussions surrounding the status of autism itself, genetic research on autism genes generates specific ethical questions that are not completely analogous to the ethical issues of genetic research in general.
METHOD: In order to map ethical issues surrounding research on autism genes, as experienced by professionals in the field of autism, we interviewed 15 Belgian professionals.
RESULTS: We found that respondents believed that the heterogeneity of the autism phenotype affects the ethics of research on several levels. It affects issues regarding who to include in research on autism genes, regarding what the aim is of such studies, and how the research is done.
CONCLUSIONS: Although genetic research on autism genes is proliferating, a systematic ethical reflection and protocol is missing. With this study we have shown that autism professionals in Belgium express both skepticism and hope with regard to genetic research and raise important points with regard to the effect that the complexity of autism has on research aims and methodology.

PMID: 26721322 [PubMed - as supplied by publisher]

Genetics and psychotic disorders: a fresh look at consanguinity.

January 2, 2016 - 7:45am

Genetics and psychotic disorders: a fresh look at consanguinity.

Eur J Med Genet. 2015 Dec 22;

Authors: Dahdouh-Guermouche A, Taleb M, Blecha L, Benyamina A

Abstract
Consanguineous unions refer to marriages between related individuals who share a common ancestor. These unions are still commonplace in certain regions of the world such as the southern coast of the Mediterranean, throughout the Middle East and South-East Asia. According to available data, couples with second-degree relations or closer and their offspring currently represent 10.4% of the world's population, thus resulting in increased frequencies of autosomal recessive disorders. Furthermore, consanguinity may be implicated in the increased frequency of multifactorial pathologies such as mental disorders. The few existing epidemiological studies in consanguineous and/or geographically isolated populations confirm that there is a significant association between consanguinity and mental disorders and a higher risk of schizophrenia or bipolar disorders among offspring from consanguineous couples. There exists a strong and complex genetic component in the predisposition to psychotic disorders that has been confirmed in numerous studies. However, the genetic basis of these disorders remains poorly understood. GWAS studies (Genome Wide Association Studies) over the past 10 years have identified a few weak associations, thus refuting the "common diseases-common variants" hypothesis. A model implicating numerous rare variants has been supported by the recent discovery of CNVs (Copy Number Variants) and their statistically significant association with psychiatric disorders such as schizophrenia, bipolar disorders and autism. The study of consanguineous families may contribute to identifying rare variants in homogenous populations who have conserved certain alleles. Major developments in molecular biology techniques would facilitate these studies as well as contributing to identifying major genes. These results emphasize the need for genetic counseling in high-risk communities and the importance of implementing preventive actions and raising awareness concerning the risk of consanguineous unions.

PMID: 26721321 [PubMed - as supplied by publisher]

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.

January 2, 2016 - 7:45am
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Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.

Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):E5308-17

Authors: Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K

Abstract
Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) prion causes the rare human disorder Creutzfeldt-Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T-YFP) and TgM83(+/-) mice expressing α-synuclein (A53T). The TgM83(+/-) mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83(+/+) mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83(+/-) mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T-YFP in cultured cells, whereas none of six Parkinson's disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

PMID: 26324905 [PubMed - indexed for MEDLINE]

Genotype-first analysis of the 16p11.2 deletion defines a new type of "autism".

January 2, 2016 - 7:45am
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Genotype-first analysis of the 16p11.2 deletion defines a new type of "autism".

Biol Psychiatry. 2015 May 1;77(9):769-71

Authors: Duyzend MH, Eichler EE

PMID: 25843334 [PubMed - indexed for MEDLINE]

DSM-5 and psychiatric genetics - round hole, meet square peg.

January 2, 2016 - 7:45am
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DSM-5 and psychiatric genetics - round hole, meet square peg.

Biol Psychiatry. 2015 May 1;77(9):766-8

Authors: Buxbaum JD

PMID: 25843333 [PubMed - indexed for MEDLINE]

Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity.

January 2, 2016 - 7:45am
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Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity.

Neuropharmacology. 2015 Jun;93:274-84

Authors: Gupta SC, Yadav R, Pavuluri R, Morley BJ, Stairs DJ, Dravid SM

Abstract
The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC and hippocampus. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2B-containing receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders such as autism.

PMID: 25721396 [PubMed - indexed for MEDLINE]

Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice.

January 1, 2016 - 7:44am
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Hippocampal neuroligin-2 links early-life stress with impaired social recognition and increased aggression in adult mice.

Psychoneuroendocrinology. 2015 May;55:128-43

Authors: Kohl C, Wang XD, Grosse J, Fournier C, Harbich D, Westerholz S, Li JT, Bacq A, Sippel C, Hausch F, Sandi C, Schmidt MV

Abstract
Early-life stress is a key risk factor for the development of neuropsychiatric disorders later in life. Neuronal cell adhesion molecules have been strongly implicated in the pathophysiology of psychiatric disorders and in modulating social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic synapses, and is involved in synaptic stabilization and maturation. Alterations in neuroligin-2 expression have previously been associated with changes in social behavior linked to psychiatric disorders, including schizophrenia and autism. In this study, we show that early-life stress, induced by limited nesting and bedding material, leads to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of hippocampal neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood mimics early-life stress-induced alterations in social behavior and social cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus attenuates the early-life stress-induced behavioral changes. Our results highlight the importance of neuroligin-2 in mediating early-life stress effects on social behavior and social cognition and its promising role as a novel therapeutic target for neuropsychiatric disorders.

PMID: 25765754 [PubMed - indexed for MEDLINE]

Impact of cross-disorder polygenic risk on frontal brain activation with specific effect of schizophrenia risk.

January 1, 2016 - 7:44am
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Impact of cross-disorder polygenic risk on frontal brain activation with specific effect of schizophrenia risk.

Schizophr Res. 2015 Feb;161(2-3):484-9

Authors: Whalley HC, Hall L, Romaniuk L, Macdonald A, Lawrie SM, Sussmann JE, McIntosh AM

Abstract
Evidence suggests that there is shared genetic aetiology across the major psychiatric disorders conferred by additive effects of many common variants. Measuring their joint effects on brain function may identify common neural risk mechanisms. We investigated the effects of a cross-disorder polygenic risk score (PGRS), based on additive effects of genetic susceptibility to the five major psychiatric disorders, on brain activation during performance of a language-based executive task. We examined this relationship in healthy individuals with (n=82) and without (n=57) a family history of bipolar disorder to determine whether this effect was additive or interactive dependent on the presence of family history. We demonstrate a significant interaction for polygenic loading×group in left lateral frontal cortex (BA9, BA6). Further examination indicated that this was driven by a significant positive correlation in those without a family history (i.e. healthy unrelated volunteers), with no significant relationships in the familial group. We then examined the effect of the individual diagnoses contributing to the PGRS to determine evidence of disorder-specificity. We found a significant association with the schizophrenia polygenic score only, with no other significant relationships. These findings indicate differences in left lateral frontal brain activation in association with increased cross-disorder PGRS in individuals without a family history of psychiatric illness. Lack of effects in the familial group may reflect epistatic effects, shared environmental influences or effects not captured by the PGRS. The specific relationship with loading for schizophrenia is notably consistent with frontal cortical inefficiency as a circumscribed phenotype of psychotic disorders.

PMID: 25468172 [PubMed - indexed for MEDLINE]

Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly.

January 1, 2016 - 7:44am
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Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly.

Biol Psychiatry. 2015 May 1;77(9):805-15

Authors: Aceti M, Creson TK, Vaissiere T, Rojas C, Huang WC, Wang YX, Petralia RS, Page DT, Miller CA, Rumbaugh G

Abstract
BACKGROUND: Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders.
METHODS: A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development.
RESULTS: Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults.
CONCLUSIONS: Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders.

PMID: 25444158 [PubMed - indexed for MEDLINE]

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