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Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for In Vivo Studies.

September 20, 2016 - 8:23am
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Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for In Vivo Studies.

J Vis Exp. 2015;(98)

Authors: Vogt D, Wu PR, Sorrells SF, Arnold C, Alvarez-Buylla A, Rubenstein JL

Abstract
GABAergic cortical interneurons, derived from the embryonic medial and caudal ganglionic eminences (MGE and CGE), are functionally and morphologically diverse. Inroads have been made in understanding the roles of distinct cortical interneuron subgroups, however, there are still many mechanisms to be worked out that may contribute to the development and maturation of different types of GABAergic cells. Moreover, altered GABAergic signaling may contribute to phenotypes of autism, schizophrenia and epilepsy. Specific Cre-driver lines have begun to parcel out the functions of unique interneuron subgroups. Despite the advances in mouse models, it is often difficult to efficiently study GABAergic cortical interneuron progenitors with molecular approaches in vivo. One important technique used to study the cell autonomous programming of these cells is transplantation of MGE cells into host cortices. These transplanted cells migrate extensively, differentiate, and functionally integrate. In addition, MGE cells can be efficiently transduced with lentivirus immediately prior to transplantation, allowing for a multitude of molecular approaches. Here we detail a protocol to efficiently transduce MGE cells before transplantation for in vivo analysis, using available Cre-driver lines and Cre-dependent expression vectors. This approach is advantageous because it combines precise genetic manipulation with the ability of these cells to disperse after transplantation, permitting greater cell-type specific resolution in vivo.

PMID: 25938985 [PubMed - indexed for MEDLINE]

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism.

September 20, 2016 - 8:23am
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Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism.

Eur J Hum Genet. 2016 Jan;24(1):59-65

Authors: Machado CO, Griesi-Oliveira K, Rosenberg C, Kok F, Martins S, Passos-Bueno MR, Sertie AL

Abstract
Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuron-specific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.

PMID: 25898924 [PubMed - indexed for MEDLINE]

Sociodemographic Disparities in Intervention Service Utilization in Families of Children with Autism Spectrum Disorder.

September 19, 2016 - 8:19am

Sociodemographic Disparities in Intervention Service Utilization in Families of Children with Autism Spectrum Disorder.

J Autism Dev Disord. 2016 Sep 17;

Authors: Nguyen CT, Krakowiak P, Hansen R, Hertz-Picciotto I, Angkustsiri K

Abstract
This study investigates whether sociodemographic factors are associated with utilization of intervention services for children with autism spectrum disorder (ASD) enrolled in the Childhood Autism Risks from Genetics and the Environment Study. Maternal ethnicity, insurance status, and education for 696 families of children with ASD were available. Children of Black mothers entered intervention earlier compared to White mothers (2 vs. 2.6 years; p = 0.001). Having public insurance was associated with receiving <15 h/week of individual services, while having a Bachelor degree was associated with receiving <15 h/week of classroom-based services. These differences suggest that SES may be a factor in utilization of services. Efforts should be made to ensure that interventions offered are culturally and linguistically accessible.

PMID: 27639855 [PubMed - as supplied by publisher]

Prenatal diagnosis of 17q12 deletion syndrome: from fetal hyperechogenic kidneys to high risk for autism.

September 17, 2016 - 8:16am

Prenatal diagnosis of 17q12 deletion syndrome: from fetal hyperechogenic kidneys to high risk for autism.

Prenat Diagn. 2016 Sep 16;

Authors: Gilboa Y, Perlman S, Pode-Shakked N, Pode-Shakked B, Shrim A, Azaria-Lahav E, Dekel B, Yonath H, Berkenstadt M, Achiron R

Abstract
OBJECTIVE: The linkage between 17q12 microdeletions, renal anomalies and higher risk for neuro-developmental disorders is well described in the literature. The current study presents prenatal diagnosis of normal-sized hyperechogenic fetal kidneys leading to the diagnosis of 17q12 deletion syndrome and autistic spectrum disorder.
METHODS: Over a period of nine years in a single referral center, seven fetuses were diagnosed with hyperechogenic renal parenchyma and followed prospectively. Amniocentesis for molecular diagnosis was performed in all cases, and subsequently five fetuses were found to harbor a 17q12 deletion by chromosomal microarray analysis. Postnatal evaluation was carried out by a developmental neurologist.
RESULTS: Five of the seven fetuses had molecular diagnosis of 17q12 deletion. One patient elected termination of pregnancy. On long term follow up all of the four children showed symptoms consistent with neurodevelopmental disorders. The two fetuses with no deletion have a normal follow up with regression of the renal hyper-echogenicity.
CONCLUSIONS: We report a strikingly high correlation between prenatal hyperechogenic kidneys, 17q12 micro deletion and autistic spectrum disorder with the advantage of optimal prenatal counseling as well as early diagnosis and intervention.

PMID: 27634641 [PubMed - as supplied by publisher]

Topoisomerases interlink genetic network underlying autism.

September 17, 2016 - 8:16am
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Topoisomerases interlink genetic network underlying autism.

Int J Dev Neurosci. 2015 Dec;47(Pt B):361-8

Authors: Vokálová L, Durdiaková J, Ostatníková D

Abstract
DNA topoisomerases belong to the group of proteins that play an important role in the organizational dynamics of the human genome. Their enzymatic activity solves topological strain rising from DNA supercoiling occurring during transcription. DNA topoisomerases are especially important for transcription of genes involved in neurodevelopment. Disruption of topoisomerase activity in animal models resulted in impaired neurodevelopment and changed brain architecture. Recent research revealed that topoisomerases induced expression of the same group of genes as those associated with autism. Transcriptional inhibition of neuronal genes during critical stages of brain development may be responsible for pathology of neurodevelopmental disorders such as autism. In this review we aim to outline the role of topoisomerase in neurodevelopment and its possible linkage to neuropathology of autism.

PMID: 26456455 [PubMed - indexed for MEDLINE]

Direct conversion of human fibroblasts to induced serotonergic neurons.

September 17, 2016 - 8:16am
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Direct conversion of human fibroblasts to induced serotonergic neurons.

Mol Psychiatry. 2016 Jan;21(1):62-70

Authors: Xu Z, Jiang H, Zhong P, Yan Z, Chen S, Feng J

Abstract
Serotonergic (5HT) neurons exert diverse and widespread functions in the brain. Dysfunction of the serotonergic system gives rise to a variety of mental illnesses including depression, anxiety, obsessive compulsive disorder, autism and eating disorders. Here we show that human primary fibroblasts were directly converted to induced serotonergic (i5HT) neurons by the expression of Ascl1, Foxa2, Lmx1b and FEV. The transdifferentiation was enhanced by p53 knockdown and appropriate culture conditions including hypoxia. The i5HT neurons expressed markers for mature serotonergic neurons, had Ca(2+)-dependent 5HT release and selective 5HT uptake, exhibited spontaneous action potentials and spontaneous excitatory postsynaptic currents. Application of serotonin significantly increased the firing rate of spontaneous action potentials, demonstrating the functional utility of i5HT neurons for studying serotonergic neurotransmission. The availability of human i5HT neurons will be very useful for research and drug discovery on many serotonin-related mental disorders.

PMID: 26216300 [PubMed - indexed for MEDLINE]

Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.

September 17, 2016 - 8:16am
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Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.

Mol Psychiatry. 2016 Jan;21(1):118-25

Authors: Tilot AK, Bebek G, Niazi F, Altemus JB, Romigh T, Frazier TW, Eng C

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a clear, but heterogeneous, genetic component. Germline mutations in the tumor suppressor Pten are a well-established risk factor for ASD with macrocephaly, and conditional Pten mouse models have impaired social behavior and brain development. Some mutations observed in patients disrupt the normally balanced nuclear-cytoplasmic localization of the Pten protein, and we developed the Pten(m3m4) model to study the effects of a cytoplasm-predominant Pten. In this model, germline mislocalization of Pten causes inappropriate social behavior with intact learning and memory, a profile reminiscent of high-functioning ASD. These animals also exhibit histological evidence of neuroinflammation and expansion of glial populations by 6 weeks of age. We hypothesized that the neural transcriptome of this model would be altered in a manner that could inform human idiopathic ASD, a constitutional condition. Using total RNA sequencing, we found progressive disruption of neural gene expression in Pten(m3m4) mice from 2-6 weeks of age, involving both immune and synaptic pathways. These alterations include downregulation of many highly coexpressed human ASD-susceptibility genes. Comparison with a human cortical development coexpression network revealed that genes disrupted in Pten(m3m4) mice were enriched in the same areas as those of human ASD. Although Pten-related ASD is relatively uncommon, our observations suggest that the Pten(m3m4) model recapitulates multiple molecular features of human ASD, and that Pten operates far upstream of common pathways within ASD pathogenesis.

PMID: 25754085 [PubMed - indexed for MEDLINE]

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

September 17, 2016 - 8:16am
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Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

Mol Psychiatry. 2016 Jan;21(1):126-32

Authors: van Bon BW, Coe BP, Bernier R, Green C, Gerdts J, Witherspoon K, Kleefstra T, Willemsen MH, Kumar R, Bosco P, Fichera M, Li D, Amaral D, Cristofoli F, Peeters H, Haan E, Romano C, Mefford HC, Scheffer I, Gecz J, de Vries BB, Eichler EE

Abstract
Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

PMID: 25707398 [PubMed - indexed for MEDLINE]

Common polygenic variation and risk for childhood-onset schizophrenia.

September 17, 2016 - 8:16am
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Common polygenic variation and risk for childhood-onset schizophrenia.

Mol Psychiatry. 2016 Jan;21(1):94-6

Authors: Ahn K, An SS, Shugart YY, Rapoport JL

Abstract
Childhood-onset schizophrenia (COS) is a rare and severe form of the disorder, with more striking abnormalities with respect to prepsychotic developmental disorders and abnormities in the brain development compared with later-onset schizophrenia. We previously documented that COS patients, compared with their healthy siblings and with adult-onset patients (AOS), carry significantly more rare chromosomal copy number variations, spanning large genomic regions (>100 kb) (Ahn et al. 2014). Here, we interrogated the contribution of common polygenic variation to the genetic susceptibility for schizophrenia. We examined the association between a direct measure of genetic risk of schizophrenia in 130 COS probands and 103 healthy siblings. Using data from the schizophrenia and autism GWAS of the Psychiatric Genomic Consortia, we selected three risk-related sets of single nucleotide polymorphisms from which we conducted polygenic risk score comparisons for COS probands and their healthy siblings. COS probands had higher genetic risk scores of both schizophrenia and autism than their siblings (P<0.05). Given the small sample size, these findings suggest that COS patients have more salient genetic risk than do AOS.

PMID: 25510512 [PubMed - indexed for MEDLINE]

Changing ASD-ADHD symptom co-occurrence across the lifespan with adolescence as crucial time window: illustrating the need to go beyond childhood.

September 16, 2016 - 8:14am

Changing ASD-ADHD symptom co-occurrence across the lifespan with adolescence as crucial time window: illustrating the need to go beyond childhood.

Neurosci Biobehav Rev. 2016 Sep 11;

Authors: Hartman CA, Geurts HM, Franke B, Buitelaar JK, Rommelse NN

Abstract
Literature on the co-occurrence between Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) is strongly biased by a focus on childhood age. A review of the adolescent and adult literature was made on core and related symptoms of ADHD and ASD. In addition, an empirical approach was used including 17,173 ASD-ADHD symptom ratings from participants aged 0 to 84 years. Results indicate that ASD/ADHD constellations peak during adolescence and are lower in early childhood and old age. We hypothesize that on the border of the expected transition to independent adulthood, ASD and ADHD co-occur most because social adaptation and EF skills matter most. Lower correlations in childhood and older age may be due to more diffuse symptoms reflecting respectively still differentiating and de-differentiating EF functions. We plea for a strong research focus in adolescence which may -after early childhood- be a second crucial time window for catching-up pattern explaining more optimal outcomes. A full lifespan approach into old age.

PMID: 27629802 [PubMed - as supplied by publisher]

[Clinical characteristics and prognosis analysis of vitamin B6 responsive infantile spasms].

September 16, 2016 - 8:14am
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[Clinical characteristics and prognosis analysis of vitamin B6 responsive infantile spasms].

Zhonghua Er Ke Za Zhi. 2016 Feb;54(2):141-4

Authors: Xue J, Yang Z, Wu Y, Xiong H, Zhang Y, Liu X

Abstract
OBJECTIVE: To analyze clinical characteristics, treatment and prognosis in a cohort of children with vitamin B6 responsive infantile spasms.
METHOD: Ten patients were diagnosed as vitamin B6 responsive infantile spasms in Peking University First Hospital between January 2012 and May 2015.The clinical manifestations, diagnosis and treatment process, video-electroencephalogram, magnetic resonance imaging (MRI), epilepsy related genes and prognosis were retrospectively analyzed.
RESULT: Of the 10 patients, 5 were male, and 5 were female. Eight of them were normal at birth, and the other 2 patients had intracranial hemorrhage or anoxia.The age of epilepsy onset was from 3.5 to 8.0 months.All patients presented spasms primarily.Interictal electroencephalogram (EEG) showed hypsarrhythmia at seizures onset. MRI showed normal in 8 patients, and subarachnoid hemorrhage or multiple encephalomalacia foci after hemorrhage respectively in the other 2 patients. The results of blood biochemical, cerebrospinal fluid examination and urinary metabolic screening were negative. Epilepsy related genes including ALDH7A1 gene analysis showed wild type in all patients. Two patients were classified as symptomatic and eight might be idiopathic or cryptogenic. The initial dose of vitamin B6 was 10.0 mg/(kg·d). The interval between seizures onset and taking vitamin B6 was 0 to 4.0 months. Seizures disappeared completely within a week after administration of vitamin B6 in 9 patients and in 1.5 months in one patient.Of the 8 patients whose seizures were controlled completely during the follow-up period, 7 patients' EEG recovered within 1.5 to 4.0 months and then continued to be normal. The EEG of the rest of a patient returned to normal, but showed abnormal discharges after stopping taking vitamin B6. Two patients' EEG continued abnormal and seizures recurred due to vitamin B6 withdrawal. At the last follow-up, seizures were controlled in all patients. Drug treatment in one case had stopped. Vitamin B6 was used in 9 patients at a dose of 0.4 to 10.0 mg/(kg·d). Among them, vitamin B6 monotherapy or coadministration with one low dose antiepileptic drug was applied in 6 or 3 patients respectively. The psychomotor development was normal in 5 patients, mild delay in 3 patients, and severe delay in 2 patients with autism behavior. Of the 2 symptomatic patients, one developed normally and the other showed severe delay.
CONCLUSION: Vitamin B6 might have effects on both idiopathic or cryptogenic and symptomatic patients, especially for the former. High dose vitamin B6 should be first tried in all patients with infantile spasms. Patients who had response to vitamin B6 could be controlled within a short time and might have better outcomes. Seizures were not easy to relapse in those whose seizures were controlled and EEG recovered completely. Vitamin B6 could be gradually reduced during the course and might be withdrawn in the future. The recurrence of seizures was closely related to EEG abnormality.

PMID: 26875466 [PubMed - indexed for MEDLINE]

Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice.

September 16, 2016 - 8:14am
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Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice.

Behav Brain Res. 2016 Jan 1;296:47-52

Authors: Kyzar EJ, Stewart AM, Kalueff AV

Abstract
Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert(+/-) mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert(+/-) mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert(+/+) and Sert(+/-) mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert(+/-) mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice.

PMID: 26340513 [PubMed - indexed for MEDLINE]

Different attentional abilities among inbred mice strains using virtual object recognition task (VORT): SNAP25⁺/⁻ mice as a model of attentional deficit.

September 16, 2016 - 8:14am
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Different attentional abilities among inbred mice strains using virtual object recognition task (VORT): SNAP25⁺/⁻ mice as a model of attentional deficit.

Behav Brain Res. 2016 Jan 1;296:393-400

Authors: Braida D, Ponzoni L, Matteoli M, Sala M M

Abstract
Autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, Alzheimer's and Parkinson's disease are characterized by attentional deficits. In the present study we first applied the virtual object recognition test (VORT), where 3D objects were replaced with highly discriminated geometrical shapes and presented on two 3.5-inch widescreen displays, in different inbred mice strains (C57BL/6N, DBA/2J, BALB/cJ), in comparison with the standard object recognition test (NOR). In both NOR and VORT, there was a progressive decay of performance in terms of reduced discrimination index from 5 min to 72 h of inter-trial delay in all strains. However, BALB/cJ inbred mice showed a better long lasting performance than C57BL/6N and DBA/2J, when tested in NOR. In VORT, BALB/cJ showed the best performance. Total exploration time was always higher in BALB/cJ than C57BL/6N and DBA/2J mice. C57BL/6N were less explorative strain than DBA/2J and BALB/cJ mice. When VORT was applied to SNAP-25(+/-) mice, an impairment in both NOR and VORT was shown. However, when moving shapes were applied, these heterozygous mice improved their performance, suggesting that the introduction of motion is a strong cue that makes the task more valuable to study attention deficits. Taken together, these data indicate that VORT provides a useful and rapid tool to identify the attentional deficit in different inbred strains and genetically modified mice, enhancing the value of psychiatric mouse models.

PMID: 26300453 [PubMed - indexed for MEDLINE]

Effects of Exposure to Bisphenol A and Ethinyl Estradiol on the Gut Microbiota of Parents and Their Offspring in a Rodent Model.

September 15, 2016 - 8:11am

Effects of Exposure to Bisphenol A and Ethinyl Estradiol on the Gut Microbiota of Parents and Their Offspring in a Rodent Model.

Gut Microbes. 2016 Sep 13;:0

Authors: Javurek AB, Spollen WG, Johnson SA, Bivens NJ, Bromert KH, Givan SA, Rosenfeld CS

Abstract
Gut dysbiosis may result in various diseases, such as metabolic and neurobehavioral disorders. Exposure to endocrine disrupting chemicals (EDCs), including bisphenol A (BPA) and ethinyl estradiol (EE), especially during development, may also increase the risk for such disorders. An unexplored possibility is that EDC-exposure might alter the gut microbial composition. Gut flora and their products may thus be mediating factors for the harmful effects of these chemicals. To examine the effects of EDCs on the gut microbiome, female and male monogamous and biparental California mice (Peromyscus californicus) were exposed to BPA (50 mg/kg feed weight) or EE (0.1 ppb) or control diet from periconception through weaning. 16s rRNA sequencing was performed on bacterial DNA isolated from fecal samples, and analyses performed for P0 and F1 males and females. Both BPA and EE induced generational and sex-dependent gut microbiome changes. Many of the bacteria, e.g. Bacteroides, Mollicutes, Prevotellaceae, Erysipelotrichaceae, Akkermansia, Methanobrevibacter, Sutterella, whose proportions increase with exposure to BPA or EE in the P0 or F1 generation are associated with different disorders, such as inflammatory bowel disease (IBD), metabolic disorders, and colorectal cancer. However, the proportion of the beneficial bacterium, Bifidobacterium, was also elevated in fecal samples of BPA- and EE-exposed F1 females. Intestinal flora alterations were also linked to changes in various metabolic and other pathways. Thus, BPA and EE exposure may disrupt the normal gut flora, which may in turn result in systemic effects. Probiotic supplementation might be an effective means to mitigate disease-promoting effects of these chemicals.

PMID: 27624382 [PubMed - as supplied by publisher]

Cytokines profile and peripheral blood mononuclear cells morphology in Rett and autistic patients.

September 15, 2016 - 8:11am
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Cytokines profile and peripheral blood mononuclear cells morphology in Rett and autistic patients.

Cytokine. 2016 Jan;77:180-8

Authors: Pecorelli A, Cervellati F, Belmonte G, Montagner G, Waldon P, Hayek J, Gambari R, Valacchi G

Abstract
A potential role for immune dysfunction in autism spectrum disorders (ASD) has been well established. However, immunological features of Rett syndrome (RTT), a genetic neurodevelopmental disorder closely related to autism, have not been well addressed yet. By using multiplex Luminex technology, a panel of 27 cytokines and chemokines was evaluated in serum from 10 RTT patients with confirmed diagnosis of MECP2 mutation (typical RTT), 12 children affected by classic autistic disorder and 8 control subjects. The cytokine/chemokine gene expression was assessed by real time PCR on mRNA of isolated peripheral blood mononuclear cells (PBMCs). Moreover, ultrastructural analysis of PBMCs was performed using transmission electron microscopy (TEM). Significantly higher serum levels of interleukin-8 (IL-8), IL-9, IL-13 were detected in RTT compared to control subjects, and IL-15 shows a trend toward the upregulation in RTT. In addition, IL-1β and VEGF were the only down-regulated cytokines in autistic patients with respect to RTT. No difference in cytokine/chemokine profile between autistic and control groups was detected. These data were also confirmed by ELISA real time PCR. At the ultrastructural level, the most severe morphological abnormalities were observed in mitochondria of both RTT and autistic PBMCs. In conclusion, our study shows a deregulated cytokine/chemokine profile together with morphologically altered immune cells in RTT. Such abnormalities were not quite as evident in autistic subjects. These findings indicate a possible role of immune dysfunction in RTT making the clinical features of this pathology related also to the immunology aspects, suggesting, therefore, novel possible therapeutic interventions for this disorder.

PMID: 26471937 [PubMed - indexed for MEDLINE]

eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors.

September 15, 2016 - 8:11am
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eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors.

Neurobiol Dis. 2015 Nov;83:67-74

Authors: Huynh TN, Shah M, Koo SY, Faraud KS, Santini E, Klann E

Abstract
Autism spectrum disorder (ASD) is a group of heritable disorders with complex and unclear etiology. Classic ASD symptoms include social interaction and communication deficits as well as restricted, repetitive behaviors. In addition, ASD is often comorbid with intellectual disability. Fragile X syndrome (FXS) is the leading genetic cause of ASD, and is the most commonly inherited form of intellectual disability. Several mouse models of ASD and FXS exist, however the intellectual disability observed in ASD patients is not well modeled in mice. Using the Fmr1 knockout mouse and the eIF4E transgenic mouse, two previously characterized mouse models of fragile X syndrome and ASD, respectively, we generated the eIF4E/Fmr1 double mutant mouse. Our study shows that the eIF4E/Fmr1 double mutant mice display classic ASD behaviors, as well as cognitive dysfunction. Importantly, the learning impairments displayed by the double mutant mice spanned multiple cognitive tasks. Moreover, the eIF4E/Fmr1 double mutant mice display increased levels of basal protein synthesis. The results of our study suggest that the eIF4E/Fmr1 double mutant mouse may be a reliable model to study cognitive dysfunction in the context of ASD.

PMID: 26306459 [PubMed - indexed for MEDLINE]

Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders.

September 14, 2016 - 7:51am
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Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders.

Biochem Soc Trans. 2015 Dec;43(6):1259-65

Authors: Sartor F, Anderson J, McCaig C, Miedzybrodzka Z, Müller B

Abstract
Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention.

PMID: 26614670 [PubMed - indexed for MEDLINE]

Microdeletion 8q22.2-q22.3 in a 40-year-old male.

September 14, 2016 - 7:51am
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Microdeletion 8q22.2-q22.3 in a 40-year-old male.

Eur J Med Genet. 2015 Nov;58(11):569-72

Authors: Sinajon P, Gofine T, Ingram J, So J

Abstract
BACKGROUND: Interstitial deletions at chromosome 8q22.2-q22.3 have been rarely reported in the literature. To date, six patients have been described in the literature with deletions varying in size from 1.36 Mb to 6.44 Mb. These patients range in age from early childhood to early adulthood. The interstitial deletion phenotype has been described to involve moderate to severe intellectual disability, seizures and a distinct facial phenotype. We report on a 40-year-old male with a 3.351 Mb deletion at chromosome 8q22.2-q22.3 who presents with moderate intellectual disability, autism spectrum disorder, childhood seizure disorder, congenital heart defect and hearing loss. He is the oldest known patient to date.
METHODS: Array comparative genomic hybridization (aCGH) was performed on DNA extracted from peripheral blood.
CONCLUSION: This is the first report of an individual with chromosome 8q22.2-q22.3 interstitial deletion associated with congenital heart disease and hearing loss. Haploinsufficiency of the GRHL2 gene contained within the microdeletion is proposed as a candidate genetic mechanism for this patient's hearing loss.

PMID: 26455667 [PubMed - indexed for MEDLINE]

Phenotype of 7q11.23 duplication: A family clinical series.

September 13, 2016 - 7:31am

Phenotype of 7q11.23 duplication: A family clinical series.

Am J Med Genet A. 2016 Sep 12;

Authors: Earhart BA, Williams ME, Zamora I, Randolph LM, Votava-Smith JK, Marcy SN

Abstract
Duplication 7q11.23 syndrome is the reciprocal of Williams-Beuren deletion syndrome. Studies have reported a recognizable phenotype, including autism, intellectual disability, speech, and language delay, social anxiety, and behavioral difficulties in these individuals. Previous studies revealed a variety of craniofacial abnormalities, brain malformations, and cardiac abnormalities, including aortic dilation. This patient series evaluates five family members aged 2 months to 35 years, all with confirmed 7q11.23 duplication syndrome. All had characteristic craniofacial findings and joint hyperextensibility, and three experienced broken bones/fractures with minimal trauma. Other features included frequent headaches, sleep problems, hydrocephalus, and in two of the children, mildly dilated aortic root, and ascending aorta. Psychological test results reveal borderline to low average nonverbal cognitive abilities and speech and language delays. All five family members with 7q11.23 syndrome meet criteria for autism spectrum disorder. Adaptive functioning is impaired for all four children, but higher for the children's father. The infant shows developmental delays in language and motor skills, but some improvements in reciprocal social behaviors over time. Two children exhibit hyperactivity and inattention, and the father and second youngest child exhibit anxiety. This family clinical series contributes to the growing literature on the phenotype of 7q11.23 microduplication syndrome across the age range. Physicians are encouraged to urge focused medical surveillance and intensive early intervention targeting speech-language and social reciprocity. © 2016 Wiley Periodicals, Inc.

PMID: 27615053 [PubMed - as supplied by publisher]

Effects of β-diketone antibiotic mixtures on behavior of zebrafish (Danio rerio).

September 13, 2016 - 7:31am
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Effects of β-diketone antibiotic mixtures on behavior of zebrafish (Danio rerio).

Chemosphere. 2016 Feb;144:2195-205

Authors: Wang X, Zheng Y, Zhang Y, Li J, Zhang H, Wang H

Abstract
To date, few data are available on neurotoxicity of β-diketone antibiotics (DKAs) from the perspective of animal behavior. Herein, the effects of long-term DKAs exposure on zebrafish (Danio rerio) behavior were assessed for locomotor activity, anxiety, social interaction and their related molecular mechanisms. DKAs exposure to zebrafish consisted of six DKA species, including ofloxacin, ciprofloxacin, enrofloxacin, doxycycline, chlortetracycline and oxytetracycline, with equal weight concentration and equal volume. DKAs at 6.25 mg/L significantly increased the time spent in the upper portion of the test tank (+40%) and the number of line crossings (±42%), indicating occurrence of anxiolytic behavior. For conditioned place preference test, long-term DKAs exposure at 6.25 mg/L increased the number of motionless positions in the non-preferred white side (+31%), number of transitions to the white side (+221%) and time spent in the white side (+35%) in relation to the control. DKAs at 6.25 mg/L significantly increased zebrafish shoaling behavior (+38%) resulting from an anxiety-like state, but 25 mg/L DKAs exposure decreased zebrafish social cohesion (-41%) possibly due to an autism-like state. With increasing DKAs-exposure concentration, the signal intensity of (1)O2 gradually decreased, leading to insufficient energy supply and movement functional disorders. Based on GO functional annotation and metabolic pathway analysis, 11 genes closely associated with locomotor behavior were identified. Using qRT-PCR, we confirmed that DKAs exposure led to changes in the transcriptional levels of 11 locomotor-related genes. These results suggest that behavior is a potential strategy for evaluating mechanisms underlying the neurochemical basis triggered by stress in zebrafish.

PMID: 26595314 [PubMed - indexed for MEDLINE]

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