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Autism-Like Behavior and Epigenetic Changes Associated with Autism as Consequences of In Utero Exposure to Environmental Pollutants in a Mouse Model.

April 19, 2016 - 7:10am
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Autism-Like Behavior and Epigenetic Changes Associated with Autism as Consequences of In Utero Exposure to Environmental Pollutants in a Mouse Model.

Behav Neurol. 2015;2015:426263

Authors: Hill DS, Cabrera R, Wallis Schultz D, Zhu H, Lu W, Finnell RH, Wlodarczyk BJ

Abstract
We tested the hypothesis that in utero exposure to heavy metals increases autism-like behavioral phenotypes in adult animals and induces epigenetic changes in genes that have roles in the etiology of autism. Mouse dams were treated with cadmium, lead, arsenate, manganese, and mercury via drinking water from gestational days (E) 1-10. Valproic acid (VPA) injected intraperitoneally once on (E) 8.5 served as a positive control. Young male offspring were tested for behavioral deficits using four standardized behavioral assays. In this study, in utero exposure to heavy metals resulted in multiple behavioral abnormalities that persisted into adulthood. VPA and manganese induced changes in perseverative/impulsive behavior and social dominance behavior, arsenic caused changes only in perseverative/impulsive behavior, and lead induced abnormalities in social interaction in comparison to the control animals. Brain samples from Mn, Pb, and VPA treated and control animals were evaluated for changes in CpG island methylation in promoter regions and associated changes in gene expression. The Chd7 gene, essential for neural crest cell migration and patterning, was found to be hypomethylated in each experimental animal tested compared to water-treated controls. Furthermore, distinct patterns of CpG island methylation yielded novel candidate genes for further investigation.

PMID: 26586927 [PubMed - indexed for MEDLINE]

The potential role of melatonin on sleep deprivation-induced cognitive impairments: implication of FMRP on cognitive function.

April 19, 2016 - 7:10am
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The potential role of melatonin on sleep deprivation-induced cognitive impairments: implication of FMRP on cognitive function.

Neuroscience. 2015 Aug 20;301:403-14

Authors: Kwon KJ, Lee EJ, Kim MK, Jeon SJ, Choi YY, Shin CY, Han SH

Abstract
While prolonged sleep deprivation (SD) could lead to profound negative health consequences, such as impairments in vital biological functions of immunity and cognition, melatonin possesses powerful ameliorating effects against those harmful insults. Melatonin has strong antioxidant and anti-inflammatory effects that help to restore body's immune and cognitive functions. In this study, we investigated the possible role of melatonin in reversing cognitive dysfunction induced by SD in rats. Our experimental results revealed that sleep-deprived animals exhibited spatial memory impairment in the Morris water maze tasks compared with the control groups. Furthermore, there was an increased glial activation most prominent in the hippocampal region of the SD group compared to the normal control (NC) group. Additionally, markers of oxidative stress such as 4-hydroxynonenal (4-HNE) and 7,8-dihydro-8-oxo-deoxyguanine (8-oxo-dG) were significantly increased, while fragile X-mental retardation protein (FMRP) expression was decreased in the SD group. Interestingly, melatonin treatment normalized these events to control levels following SD. Our data demonstrate that SD induces oxidative stress through glial activation and decreases FMRP expression in the neurons. Furthermore, our results suggest the efficacy of melatonin for the treatment of sleep-related neuronal dysfunction, which occurs in neurological disorders such as Alzheimer's disease and autism.

PMID: 26047724 [PubMed - indexed for MEDLINE]

Tumor grafting induces changes of gut microbiota in athymic nude mice in the presence and absence of medicinal Gynostemma saponins.

April 19, 2016 - 7:10am
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Tumor grafting induces changes of gut microbiota in athymic nude mice in the presence and absence of medicinal Gynostemma saponins.

PLoS One. 2015;10(5):e0126807

Authors: Chen L, Tai WC, Brar MS, Leung FC, Hsiao WL

Abstract
Recent findings have revealed that gut microbiota plays a substantial role in modulating diseases such as autism, rheumatoid arthritis, allergies, and cancer that occur at sites distant to the gut. Athymic nude mice have been employed for tumorigenic research for decades; however, the relationships between the gut microbiome and host's response in drug treatment to the grafted tumors have not been explored. In this study, we analyzed the fecal microbiome of nonxenograft and xenograft nude mice treated with phytosaponins from a popular medicinal plant, Gynostemma pentaphyllum (Gp). Analysis of enterobacterial repetitive intergenic consensus (ERIC)-PCR data showed that the microbiota profile of xenograft mice departed from that of the nonxenograft mice. After ten days of treatment with Gp saponins (GpS), the microbiota of the treated mice was closer to the microbiota at Day 0 before the implantation of the tumor. Data obtained from 16S pyrosequencing of fecal samples reiterates the differences in microbiome between the nonxenograft and xenograft mice. GpS markedly increased the relative abundance of Clostridium cocleatum and Bacteroides acidifaciens, for which the beneficial effects on the host have been well documented. This study, for the first time, characterizes the properties of gut microbiome in nude mice responding to tumor implant and drug treatment. We also demonstrate that dietary saponins such as GpS can potentially regulate the gut microbial ecosystem by increasing the number of symbionts. Interestingly, this regulation of the gut ecosystem might, at least in part, be responsible for or contribute to the anticancer effect of GpS.

PMID: 25992551 [PubMed - indexed for MEDLINE]

Study of the serum levels of polyunsaturated fatty acids and the expression of related liver metabolic enzymes in a rat valproate-induced autism model.

April 19, 2016 - 7:10am
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Study of the serum levels of polyunsaturated fatty acids and the expression of related liver metabolic enzymes in a rat valproate-induced autism model.

Int J Dev Neurosci. 2015 Aug;44:14-21

Authors: Zhao G, Gao J, Liang S, Wang X, Sun C, Xia W, Hao Y, Li X, Cao Y, Wu L

Abstract
To investigate whether the decreased level of serum polyunsaturated fatty acids (PUFAs) in patients with autism is associated with the expression of related liver metabolic enzymes, we selected rats that were exposed to valproic acid (VPA) on embryonic day 12.5 (E12.5) as a model of autism. We observed the serum levels of PUFAs and the expression of related liver metabolic enzymes, including Δ5-desaturase, Δ6-desaturase and elongase (Elovl2), in VPA-exposed and control rats on postnatal day 35 (PND35) and conducted sex dimorphic analysis. We found that the levels of serum PUFAs and related liver metabolic enzymes in the VPA rats were significantly reduced, in association with autism-like behavioral changes, the abnormal expression of apoptosis-related proteins and hippocampal neuronal injury, compared to the control rats and showed sex difference in VPA group. This finding indicated that rats exposed to VPA at the embryonic stage may exhibit reduced synthesis of serum PUFAs due to the down-regulation of liver metabolic enzymes, thereby inducing nervous system injury and behavioral changes, which is affected by sex in the meantime.

PMID: 25916973 [PubMed - indexed for MEDLINE]

Autism spectrum disorders: Integration of the genome, transcriptome and the environment.

April 17, 2016 - 6:43am

Autism spectrum disorders: Integration of the genome, transcriptome and the environment.

J Neurol Sci. 2016 May 15;364:167-76

Authors: Vijayakumar NT, Judy MV

Abstract
Autism spectrum disorders denote a series of lifelong neurodevelopmental conditions characterized by an impaired social communication profile and often repetitive, stereotyped behavior. Recent years have seen the complex genetic architecture of the disease being progressively unraveled with advancements in gene finding technology and next generation sequencing methods. However, a complete elucidation of the molecular mechanisms behind autism is necessary for potential diagnostic and therapeutic applications. A multidisciplinary approach should be adopted where the focus is not only on the 'genetics' of autism but also on the combinational roles of epigenetics, transcriptomics, immune system disruption and environmental factors that could all influence the etiopathogenesis of the disease. ASD is a clinically heterogeneous disorder with great genetic complexity; only through an integrated multidimensional effort can modern autism research progress further.

PMID: 27084239 [PubMed - in process]

Erratum: Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals.

April 16, 2016 - 6:41am

Erratum: Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals.

Hum Genome Var. 2016;3:15046

Authors: Liu X, Kawashima M, Miyagawa T, Otowa T, Latt KZ, Thiri M, Nishida H, Sugiyama T, Tsurusaki Y, Matsumoto N, Mabuchi A, Kato N, Tokunaga K, Sasaki T

Abstract
[This corrects the article DOI: 10.1038/hgv.2015.24.][This corrects the article DOI: 10.1038/hgv.2015.24.].

PMID: 27082423 [PubMed - as supplied by publisher]

Expression of nuclear Methyl-CpG binding protein 2 (Mecp2) is dependent on neuronal stimulation and application of Insulin-like growth factor 1.

April 16, 2016 - 6:41am

Expression of nuclear Methyl-CpG binding protein 2 (Mecp2) is dependent on neuronal stimulation and application of Insulin-like growth factor 1.

Neurosci Lett. 2016 Apr 11;

Authors: Tropea D, Mortimer N, Bellini S, Molinos I, Sanfeliu A, Shovlin S, McAllister D, Gill M, Mitchell K, Corvin A

Abstract
Methyl-CpG binding protein 2 (MECP2) is a chromosome-binding protein that regulates the development and maintenance of brain circuits. Altered function of the protein product of MECP2 plays an important role in the etiology of many neurodevelopmental disorders. Mutations involving a loss of function are implicated in the etiology of Rett syndrome, intellectual disability, psychosis and severe encephalopathy. Conversely, MECP2 duplications have been identified in autism and intellectual disability. MECP2 action is dependent on neuronal function, as the DNA binding is modulated by activity, and it is phosphorylated in response to stimulation. Although MECP2 is considered a major risk factor for neurodevelopmental disorders, and it is a mediator of activity-dependent mechanisms, the expression levels in response to neuronal activity have never been measured. We studied the expression of Mecp2 protein and RNA in mice neuronal cultures in response to different stimulation conditions and in the presence of insulin-like growth factor1 (IGF1): a growth factor involved in brain development and plasticity. The stimulation protocols were selected according to their ability to induce different forms of synaptic plasticity: rapid depolarization, feed-forward plasticity (LTP, LTD) and feedback forms of plasticity (TTX, KCl). We find a significant reduction of Mecp2 protein nuclear expression in neurons in response to stimuli that induce a potentiation of neuronal response, suggesting that Mecp2 protein expression is modulated by neuronal activation. Application of IGF1 to the cultures induces an increase in the expression of Mecp2 transcript and nuclear Mecp2 protein in neurons. These results show that Mecp2 is responsive to neuronal stimulation and IGF1, and different stimuli have different effects on Mecp2 expression; this differential response may have downstream effects on functional mechanisms regulating brain development and plasticity.

PMID: 27080430 [PubMed - as supplied by publisher]

A novel anesthesia regime enables neurofunctional studies and imaging genetics across mouse strains.

April 16, 2016 - 6:41am

A novel anesthesia regime enables neurofunctional studies and imaging genetics across mouse strains.

Sci Rep. 2016;6:24523

Authors: Petrinovic MM, Hankov G, Schroeter A, Bruns A, Rudin M, von Kienlin M, Künnecke B, Mueggler T

Abstract
Functional magnetic resonance imaging (fMRI) has revolutionized neuroscience by opening a unique window that allows neurocircuitry function and pathological alterations to be probed non-invasively across brain disorders. Here we report a novel sustainable anesthesia procedure for small animal neuroimaging that overcomes shortcomings of anesthetics commonly used in rodent fMRI. The significantly improved preservation of cerebrovascular dynamics enhances sensitivity to neural activity changes for which it serves as a proxy in fMRI readouts. Excellent cross-species/strain applicability provides coherence among preclinical findings and is expected to improve translation to clinical fMRI investigations. The novel anesthesia procedure based on the GABAergic anesthetic etomidate was extensively validated in fMRI studies conducted in a range of genetically engineered rodent models of autism and strains commonly used for transgenic manipulations. Etomidate proved effective, yielded long-term stable physiology with basal cerebral blood flow of ~0.5 ml/g/min and full recovery. Cerebrovascular responsiveness of up to 180% was maintained as demonstrated with perfusion- and BOLD-based fMRI upon hypercapnic, pharmacological and sensory stimulation. Hence, etomidate lends itself as an anesthetic-of-choice for translational neuroimaging studies across rodent models of brain disorders.

PMID: 27080031 [PubMed - in process]

Glutamate synapses in human cognitive disorders.

April 16, 2016 - 6:41am
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Glutamate synapses in human cognitive disorders.

Annu Rev Neurosci. 2015 Jul 8;38:127-49

Authors: Volk L, Chiu SL, Sharma K, Huganir RL

Abstract
Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.

PMID: 25897873 [PubMed - indexed for MEDLINE]

De novo intragenic deletion of the autism susceptibility candidate 2 (AUTS2) gene in a patient with developmental delay: a case report and literature review.

April 16, 2016 - 6:41am
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De novo intragenic deletion of the autism susceptibility candidate 2 (AUTS2) gene in a patient with developmental delay: a case report and literature review.

Am J Med Genet A. 2013 Jun;161A(6):1508-12

Authors: Jolley A, Corbett M, McGregor L, Waters W, Brown S, Nicholl J, Yu S

PMID: 23650183 [PubMed - indexed for MEDLINE]

A novel inverted 17p13.3 microduplication disrupting PAFAH1B1 (LIS1) in a girl with syndromic lissencephaly.

April 16, 2016 - 6:41am
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A novel inverted 17p13.3 microduplication disrupting PAFAH1B1 (LIS1) in a girl with syndromic lissencephaly.

Am J Med Genet A. 2013 Jun;161A(6):1453-8

Authors: Classen S, Goecke T, Drechsler M, Betz B, Nickel N, Beier M, Schaper J, Karenfort M, Royer-Pokora B

Abstract
We describe a female patient with mild lissencephaly (pachygyria), severe intellectual disability, and facial dysmorphisms with an inverted 1.4 Mb microduplication of chromosome 17p13.3. The 17p13.3 microduplication syndrome is associated with mild intellectual disabiltiy and contains, among others, the PAFAH1B1 (LIS1) gene, whereas microdeletions of the same segment cause Miller-Dieker syndrome (MDS) with severe to profound retardation. The duplication identified in our patient encompasses 29 genes, including CRK and YWHAE. The proximal breakpoint of the duplication is located in the first intron of the PAFAH1B1 gene. Analysis of total RNA showed that only one PAFAH1B1 allele is expressed. Therefore, this patient has a unique alteration: a duplication including YWHAE and CRK and haploinsufficiency of PAFAH1B1. Overexpression of YWHAE is associated with macrosomia, mild developmental delay, autism and facial dysmorphisms, and deletion of PAFAH1B1 alone leads to isolated lissencephaly (ILS). The patient described here shares features with MDS, but she is affected to a lesser degree. Her facial features are similar to MDS, and she has manifestations seen in other cases with YWHAE duplication.

PMID: 23633430 [PubMed - indexed for MEDLINE]

Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.

April 16, 2016 - 6:41am
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Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.

Am J Med Genet A. 2013 Jun;161A(6):1381-5

Authors: Barone C, Bianca S, Luciano D, Di Benedetto D, Vinci M, Fichera M

Abstract
Intellectual disability affects approximately 2% of the population, with affected males outnumbering affected female, partly due to disturbances involving X-linked genes. To date >90 genes associated with X-linked intellectual disability have been identified and, among these, IL1RAPL1 (interleukin 1 receptor accessory protein-like 1), was first described and mapped to Xp21.3-22.1 in 1999. Intragenic deletions of IL1RAPL1, only rarely identified, have mostly been associated with nonspecific intellectual disability (IDX) and autism spectrum disorder. Array-CGH analysis performed in our patient with intellectual disability, mild dysmorphic signs and changes in behavior identified a 285 Kb deletion in chromosome Xp21.3-21.2, with breakpoints lying in IL1RAPL1 gene intron 2 and intron 3. This is the first patient reported in literature with deletion of only exon 3 of IL1RAPL1 gene. Our patient also exhibits bilateral progressive neurosensorial deafness, which has not been previously associated with IL1RAPL1 mutations.

PMID: 23613341 [PubMed - indexed for MEDLINE]

Additional evidence to support the role of the 20q13.33 region in susceptibility to autism.

April 16, 2016 - 6:41am
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Additional evidence to support the role of the 20q13.33 region in susceptibility to autism.

Am J Med Genet A. 2013 Jun;161A(6):1505-7

Authors: Mosca-Boidron AL, Valduga M, Thauvin-Robinet C, Lagarde N, Marle N, Henry C, Pinoit JM, Huet F, Béri-Deixheimer M, Ragon C, Gueneau L, Payet M, Callier P, Mugneret F, Jonveaux P, Faivre L

PMID: 23613186 [PubMed - indexed for MEDLINE]

Monitoring host responses to the gut microbiota.

April 15, 2016 - 9:07am
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Monitoring host responses to the gut microbiota.

ISME J. 2015 Sep;9(9):1908-15

Authors: Lichtman JS, Sonnenburg JL, Elias JE

Abstract
The gastrointestinal (GI) ecosystem is increasingly understood to be a fundamental component of health, and has been identified as a new focal point for diagnosing, correcting and preventing countless disorders. Shotgun DNA sequencing has emerged as the dominant technology for determining the genetic and microbial composition of the gut microbiota. This technology has linked microbiota dysbioses to numerous GI diseases including inflammatory bowel disease, obesity and allergy, and to non-GI diseases like autism and depression. The importance of establishing causality in the deterioration of the host-microbiota relationship is well appreciated; however, discovery of candidate molecules and pathways that underlie mechanisms remains a major challenge. Targeted approaches, transcriptional assays, cytokine panels and imaging analyses, applied to animals, have yielded important insight into host responses to the microbiota. However, non-invasive, hypothesis-independent means of measuring host responses in humans are necessary to keep pace with similarly unbiased sequencing efforts that monitor microbes. Mass spectrometry-based proteomics has served this purpose in many other fields, but stool proteins exist in such diversity and dynamic range as to overwhelm conventional proteomics technologies. Focused analysis of host protein secretion into the gut lumen and monitoring proteome-level dynamics in stool provides a tractable route toward non-invasively evaluating dietary, microbial, surgical or pharmacological intervention efficacies. This review is intended to guide GI biologists and clinicians through the methods currently used to elucidate host responses in the gut, with a specific focus on mass spectrometry-based shotgun proteomics applied to the study of host protein dynamics within the GI ecosystem.

PMID: 26057846 [PubMed - indexed for MEDLINE]

New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants.

April 14, 2016 - 8:39am
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New insights in the interpretation of array-CGH: autism spectrum disorder and positive family history for intellectual disability predict the detection of pathogenic variants.

Ital J Pediatr. 2016;42(1):39

Authors: Cappuccio G, Vitiello F, Casertano A, Fontana P, Genesio R, Bruzzese D, Ginocchio VM, Mormile A, Nitsch L, Andria G, Melis D

Abstract
BACKGROUND: Array-CGH (aCGH) is presently used into routine clinical practice for diagnosis of patients with intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorder (ASD). ACGH could detect small chromosomal imbalances, copy number variations (CNVs), and closely define their size and gene content. ACGH detects pathogenic imbalances in 14-20 % of patients with ID. The aims of this study were: to establish clinical clues potentially associated with pathogenic CNVs and to identify cytogenetic indicators to predict the pathogenicity of the variants of uncertain significance (VOUS) in a large cohort of paediatric patients.
METHODS: We enrolled 214 patients referred for either: ID, and/or ASD and/or MCA to genetic services at the Federico II University of Naples, Department of Translational Medicine. For each patient we collected clinical and imaging data. All the patients were tested with aCGH or as first-tier test or as part of a wider diagnostic work-up.
RESULTS: Pathologic data were detected in 65 individuals (30 %) and 46 CNVs revealed a known syndrome. The pathological CNVs were usually deletions showing the highest gene-dosage content. The positive family history for ID/ASD/MCA and ASD were good indicators for detecting pathological chromosomal rearrangements. Other clinical features as eyes anomalies, hearing loss, neurological signs, cutaneous dyscromia and endocrinological problems seem to be potential predictors of pathological CNVs. Among patients carrying VOUS we analyzed genetic features including CNVs size, presence of deletion or duplication, genic density, multiple CNVs, to clinical features. Higher gene density was found in patients affected by ID. This result suggest that higher gene content has more chances to include pathogenic gene involved and causing ID in these patients.
CONCLUSION: Our study suggest the use of aCGH as first-tier test in patients with neurdevelopmental phenotypes. The inferred results have been used for building a flow-chart to be applied for children with ID.

PMID: 27072107 [PubMed - in process]

Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.

April 14, 2016 - 8:39am
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Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.

Hum Genet. 2015 Nov;134(11-12):1163-82

Authors: Ishibashi M, Manning E, Shoubridge C, Krecsmarik M, Hawkins TA, Giacomotto J, Zhao T, Mueller T, Bader PI, Cheung SW, Stankiewicz P, Bain NL, Hackett A, Reddy CC, Mechaly AS, Peers B, Wilson SW, Lenhard B, Bally-Cuif L, Gecz J, Becker TS, Rinkwitz S

Abstract
Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease.

PMID: 26337422 [PubMed - indexed for MEDLINE]

SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation.

April 14, 2016 - 8:39am
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SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation.

Nat Commun. 2015;6:7728

Authors: Tang LT, Craig TJ, Henley JM

Abstract
Synapsins are key components of the presynaptic neurotransmitter release machinery. Their main role is to cluster synaptic vesicles (SVs) to each other and anchor them to the actin cytoskeleton to establish the reserve vesicle pool, and then release them in response to appropriate membrane depolarization. Here we demonstrate that SUMOylation of synapsin Ia (SynIa) at K687 is necessary for SynIa function. Replacement of endogenous SynIa with a non-SUMOylatable mutant decreases the size of the releasable vesicle pool and impairs stimulated SV exocytosis. SUMOylation enhances SynIa association with SVs to promote the efficient reclustering of SynIa following neuronal stimulation and maintain its presynaptic localization. The A548T mutation in SynIa is strongly associated with autism and epilepsy and we show that it leads to defective SynIa SUMOylation. These results identify SUMOylation as a fundamental regulator of SynIa function and reveal a novel link between reduced SUMOylation of SynIa and neurological disorders.

PMID: 26173895 [PubMed - indexed for MEDLINE]

Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators.

April 14, 2016 - 8:39am
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Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators.

Cell Rep. 2015 Jun 9;11(9):1400-13

Authors: Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, Ma K, Dietz DM, Kajiwara Y, Buxbaum JD, Yan Z

Abstract
Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging, and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDA receptor (NMDAR) synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a strategy for autism treatment.

PMID: 26027926 [PubMed - indexed for MEDLINE]

The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study.

April 14, 2016 - 8:39am
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The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study.

PLoS One. 2015;10(5):e0125633

Authors: Gdalyahu A, Lazaro M, Penagarikano O, Golshani P, Trachtenberg JT, Geschwind DH, Gescwind DH

Abstract
The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry.

PMID: 25951243 [PubMed - indexed for MEDLINE]

Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment.

April 14, 2016 - 8:39am
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Autism and Intellectual Disability-Associated KIRREL3 Interacts with Neuronal Proteins MAP1B and MYO16 with Potential Roles in Neurodevelopment.

PLoS One. 2015;10(4):e0123106

Authors: Liu YF, Sowell SM, Luo Y, Chaubey A, Cameron RS, Kim HG, Srivastava AK

Abstract
Cell-adhesion molecules of the immunoglobulin superfamily play critical roles in brain development, as well as in maintaining synaptic plasticity, the dysfunction of which is known to cause cognitive impairment. Recently dysfunction of KIRREL3, a synaptic molecule of the immunoglobulin superfamily, has been implicated in several neurodevelopmental conditions including intellectual disability, autism spectrum disorder, and in the neurocognitive delay associated with Jacobsen syndrome. However, the molecular mechanisms of its physiological actions remain largely unknown. Using a yeast two-hybrid screen, we found that the KIRREL3 extracellular domain interacts with brain expressed proteins MAP1B and MYO16 and its intracellular domain can potentially interact with ATP1B1, UFC1, and SHMT2. The interactions were confirmed by co-immunoprecipitation and colocalization analyses of proteins expressed in human embryonic kidney cells, mouse neuronal cells, and rat primary neuronal cells. Furthermore, we show KIRREL3 colocalization with the marker for the Golgi apparatus and synaptic vesicles. Previously, we have shown that KIRREL3 interacts with the X-linked intellectual disability associated synaptic scaffolding protein CASK through its cytoplasmic domain. In addition, we found a genomic deletion encompassing MAP1B in one patient with intellectual disability, microcephaly and seizures and deletions encompassing MYO16 in two unrelated patients with intellectual disability, autism and microcephaly. MAP1B has been previously implicated in synaptogenesis and is involved in the development of the actin-based membrane skeleton. MYO16 is expressed in hippocampal neurons and also indirectly affects actin cytoskeleton through its interaction with WAVE1 complex. We speculate KIRREL3 interacting proteins are potential candidates for intellectual disability and autism spectrum disorder. Moreover, our findings provide further insight into understanding the molecular mechanisms underlying the physiological action of KIRREL3 and its role in neurodevelopment.

PMID: 25902260 [PubMed - indexed for MEDLINE]

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