pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 2 hours 56 min ago

Identification of differentially expressed microRNAs across the developing human brain.

April 16, 2015 - 7:39am
Related Articles

Identification of differentially expressed microRNAs across the developing human brain.

Mol Psychiatry. 2014 Jul;19(7):848-52

Authors: Ziats MN, Rennert OM

Abstract
We present a spatio-temporal assessment of microRNA (miRNA) expression throughout early human brain development. We assessed the prefrontal cortex, hippocampus and cerebellum of 18 normal human donor brains spanning infancy through adolescence by RNA-seq. We discovered differentially expressed miRNAs and broad miRNA patterns across both temporal and spatial dimensions, and between male and female prefrontal cortex. Putative target genes of the differentially expressed miRNAs were identified, which demonstrated functional enrichment for transcription regulation, synaptogenesis and other basic intracellular processes. Sex-biased miRNAs also targeted genes related to Wnt and transforming growth factor-beta pathways. The differentially expressed miRNA targets were highly enriched for gene sets related to autism, schizophrenia, bipolar disorder and depression, but not neurodegenerative diseases, epilepsy or other adult-onset psychiatric diseases. Our results suggest critical roles for the identified miRNAs in transcriptional networks of the developing human brain and neurodevelopmental disorders.

PMID: 23917947 [PubMed - indexed for MEDLINE]

NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

April 15, 2015 - 6:06am

NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

Mol Psychiatry. 2015 Apr 14;

Authors: Schuster S, Rivalan M, Strauss U, Stoenica L, Trimbuch T, Rademacher N, Parthasarathy S, Lajkó D, Rosenmund C, Shoichet SA, Winter Y, Tarabykin V, Rosário M

Abstract
Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.42.

PMID: 25869807 [PubMed - as supplied by publisher]

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

April 15, 2015 - 6:06am
Related Articles

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):E4779-88

Authors: Mergy MA, Gowrishankar R, Gresch PJ, Gantz SC, Williams J, Davis GL, Wheeler CA, Stanwood GD, Hahn MK, Blakely RD

Abstract
Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.

PMID: 25331903 [PubMed - indexed for MEDLINE]

Modeling a Model: Mouse Genetics, 22q11.2 Deletion Syndrome, and Disorders of Cortical Circuit Development.

April 14, 2015 - 8:37am

Modeling a Model: Mouse Genetics, 22q11.2 Deletion Syndrome, and Disorders of Cortical Circuit Development.

Prog Neurobiol. 2015 Apr 9;

Authors: Meechan DW, Maynard TM, Fernandez A, Karpinski BA, Rothblat LA, LaMantia AS

Abstract
Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic "model" syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that "modeling a model", in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development.

PMID: 25866365 [PubMed - as supplied by publisher]

The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway.

April 14, 2015 - 8:37am
Related Articles

The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway.

J Neurosci. 2015 Feb 18;35(7):3190-200

Authors: Pucilowska J, Vithayathil J, Tavares EJ, Kelly C, Karlo JC, Landreth GE

Abstract
Autism spectrum disorders are complex, highly heritable neurodevelopmental disorders affecting ∼1 in 100 children. Copy number variations of human chromosomal region 16p11.2 are genetically linked to 1% of autism-related disorders. This interval contains the MAPK3 gene, which encodes the MAP kinase, ERK1. Mutations in upstream elements regulating the ERK pathway are genetically linked to autism and other disorders of cognition including the neuro-cardio-facial cutaneous syndromes and copy number variations. We report that a murine model of human 16p11.2 deletion exhibits a reduction in brain size and perturbations in cortical cytoarchitecture. We observed enhanced progenitor proliferation and premature cell cycle exit, which are a consequence of altered levels of downstream ERK effectors cyclin D1 and p27(Kip1) during mid-neurogenesis. The increased progenitor proliferation and cell cycle withdrawal resulted in premature depletion of progenitor pools, altering the number and frequency of neurons ultimately populating cortical lamina. Specifically, we found a reduced number of upper layer pyramidal neurons and an increase in layer VI corticothalamic projection neurons, reflecting the altered cortical progenitor proliferation dynamics in these mice. Importantly, we observed a paradoxical increase in ERK signaling in mid-neurogenesis in the 16p11.2del mice, which is coincident with the development of aberrant cortical cytoarchitecture. The 16p11.2del mice exhibit anxiety-like behaviors and impaired memory. Our findings provide evidence of ERK dysregulation, developmental abnormalities in neurogenesis, and behavioral impairment associated with the 16p11.2 chromosomal deletion.

PMID: 25698753 [PubMed - indexed for MEDLINE]

Dysregulation of glutamine transporter SNAT1 in Rett syndrome microglia: a mechanism for mitochondrial dysfunction and neurotoxicity.

April 14, 2015 - 8:37am
Related Articles

Dysregulation of glutamine transporter SNAT1 in Rett syndrome microglia: a mechanism for mitochondrial dysfunction and neurotoxicity.

J Neurosci. 2015 Feb 11;35(6):2516-29

Authors: Jin LW, Horiuchi M, Wulff H, Liu XB, Cortopassi GA, Erickson JD, Maezawa I

Abstract
Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously, we and others reported a role of microglia in the pathophysiology of RTT. To understand the mechanism of microglia dysfunction in RTT, we identified a MeCP2 target gene, SLC38A1, which encodes a major glutamine transporter (SNAT1), and characterized its role in microglia. We found that MeCP2 acts as a microglia-specific transcriptional repressor of SNAT1. Because glutamine is mainly metabolized in the mitochondria, where it is used as an energy substrate and a precursor for glutamate production, we hypothesize that SNAT1 overexpression in MeCP2-deficient microglia would impair the glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction. Supporting this hypothesis, we found that MeCP2 downregulation or SNAT1 overexpression in microglia resulted in (1) glutamine-dependent decrease in microglial viability, which was corroborated by reduced microglia counts in the brains of MECP2 knock-out mice; (2) proliferation of mitochondria and enhanced mitochondrial production of reactive oxygen species; (3) increased oxygen consumption but decreased ATP production (an energy-wasting state); and (4) overproduction of glutamate that caused NMDA receptor-dependent neurotoxicity. The abnormalities could be rectified by mitochondria-targeted expression of catalase and a mitochondria-targeted peptide antioxidant, Szeto-Schiller 31. Our results reveal a novel mechanism via which MeCP2 regulates bioenergetic pathways in microglia and suggest a therapeutic potential of mitochondria-targeted antioxidants for RTT.

PMID: 25673846 [PubMed - indexed for MEDLINE]

The broader autism phenotype in infancy: when does it emerge?

April 14, 2015 - 8:37am
Related Articles

The broader autism phenotype in infancy: when does it emerge?

J Am Acad Child Adolesc Psychiatry. 2014 Apr;53(4):398-407.e2

Authors: Ozonoff S, Young GS, Belding A, Hill M, Hill A, Hutman T, Johnson S, Miller M, Rogers SJ, Schwichtenberg AJ, Steinfeld M, Iosif AM

Abstract
OBJECTIVE: This study had 3 goals, which were to examine the following: the frequency of atypical development, consistent with the broader autism phenotype, in high-risk infant siblings of children with autism spectrum disorder (ASD); the age at which atypical development is first evident; and which developmental domains are affected.
METHOD: A prospective longitudinal design was used to compare 294 high-risk infants and 116 low-risk infants. Participants were tested at 6, 12, 18, 24, and 36 months of age. At the final visit, outcome was classified as ASD, Typical Development (TD), or Non-TD (defined as elevated Autism Diagnostic Observation Schedule [ADOS] score, low Mullen Scale scores, or both).
RESULTS: Of the high-risk group, 28% were classified as Non-TD at 36 months of age. Growth curve models demonstrated that the Non-TD group could not be distinguished from the other groups at 6 months of age, but differed significantly from the Low-Risk TD group by 12 months on multiple measures. The Non-TD group demonstrated atypical development in cognitive, motor, language, and social domains, with differences particularly prominent in the social-communication domain.
CONCLUSIONS: These results demonstrate that features of atypical development, consistent with the broader autism phenotype, are detectable by the first birthday and affect development in multiple domains. This highlights the necessity for close developmental surveillance of infant siblings of children with ASD, along with implementation of appropriate interventions as needed.

PMID: 24655649 [PubMed - indexed for MEDLINE]

BAP: not-quite-autism in infants.

April 14, 2015 - 8:37am
Related Articles

BAP: not-quite-autism in infants.

J Am Acad Child Adolesc Psychiatry. 2014 Apr;53(4):392-4

Authors: Pruett JR

PMID: 24655647 [PubMed - indexed for MEDLINE]

Novel interstitial 2.6 Mb deletion on 9q21 associated with multiple congenital anomalies.

April 14, 2015 - 8:37am
Related Articles

Novel interstitial 2.6 Mb deletion on 9q21 associated with multiple congenital anomalies.

Am J Med Genet A. 2014 Jan;164A(1):237-42

Authors: Pua HH, Krishnamurthi S, Farrell J, Margeta M, Ursell PC, Powers M, Slavotinek AM, Jeng LJ

Abstract
Array comparative genomic hybridization (aCGH) is now commonly used to identify copy number changes in individuals with developmental delay, intellectual disabilities, autism spectrum disorders, and/or multiple congenital anomalies. We report on an infant with multiple congenital anomalies and a novel 2.6 Mb interstitial deletion within 9q21.32q21.33 detected by aCGH. Her clinical presentation included dysmorphic craniofacial features, cleft palate, atrial septal defect, bicornuate uterus, bilateral hip dislocation, hypotonia, and recurrent pneumonia. Parental aCGH studies were negative for copy loss in this region. To our knowledge, no similar deletions have been reported in available databases or published literature. This deletion encompasses 12 genes, and prediction algorithms as well as experimental data suggest that a subset is likely to be haploinsufficient. Included are a neurotrophin receptor (NKG2D), a gene implicated in cilia function (KIF27), an adaptor protein important for ubiquitin-dependent protein quality control (UBQLN1), a gene important for transcription and signaling (HNRNPK), and a gene involved in maintaining genomic stability (RMI1). Identifying additional patients with similar copy losses and further study of these genes will contribute to a better understanding of the pathophysiology of multiple congenital anomalies.

PMID: 24501764 [PubMed - indexed for MEDLINE]

The promising trajectory of autism therapeutics discovery.

April 14, 2015 - 8:37am
Related Articles

The promising trajectory of autism therapeutics discovery.

Drug Discov Today. 2014 Jul;19(7):838-44

Authors: Silverman JL, Crawley JN

Abstract
Pharmacological interventions for neurodevelopmental disorders are increasingly tractable. Autism is a neurodevelopmental disorder that affects approximately 1% of the population. Currently, the standard of care is early behavioral therapy. No approved medical treatments for the diagnostic symptoms are available. Strong evidence for genetic causes of autism implicates proteins that mediate synaptic transmission and structure. Mouse models with targeted mutations in these synaptic genes display behavioral symptoms relevant to the social communication abnormalities and repetitive behaviors that define autism spectrum disorder (ASD), along with biological abnormalities in synaptic physiology and morphology. As we discuss here, promising pharmacological targets, emerging from the mouse model studies, are now being pursued in early clinical trials. Thus, a high-prevalence disorder that was previously considered to be medically untreatable is now moving into the therapeutic arena.

PMID: 24362109 [PubMed - indexed for MEDLINE]

A clinical study of patients with pericentromeric deletion and duplication within 16p12.2-p11.2.

April 14, 2015 - 8:37am
Related Articles

A clinical study of patients with pericentromeric deletion and duplication within 16p12.2-p11.2.

Am J Med Genet A. 2014 Jan;164A(1):213-9

Authors: Okamoto N, Fujii T, Tanaka J, Saito K, Matsui T, Harada N

Abstract
The short arm of chromosome 16 is rich in segmental duplications that result in chromosomal rearrangements through non-allelic homologous recombination. Several syndromes resulting from microdeletions or microduplications in this region have been reported. The chromosome 16p12.2-p11.2 deletion syndrome, 7.1- to 8.7-Mb [OMIM#613604] is characterized by minor facial anomalies, feeding difficulties, a significant delay in speech development, and recurrent ear infections. Reciprocal duplications of 16p12.2-p11.2 have been reported in some patients with autism. We identified a patient with a 16p12.2-p11.2 deletion and a patient with a 16p12.2-p11.2 duplication using oligonucleotide SNP array. The patient with the deletion showed severe developmental delay without autism. The patient with the deletion shared clinical features with previously reported patients. The patient with the duplication showed mild developmental delay and autism. She had dysmorphic features including a round face, a large mouth, and relative macrocephaly. We reviewed the reports of the two syndromes and compared the clinical manifestations. The 16p12.2-p11.2 duplication syndrome is a new syndrome with autism spectral disorders and dysmorphic features.

PMID: 24259393 [PubMed - indexed for MEDLINE]

A case of 14q11.2 microdeletion with autistic features, severe obesity and facial dysmorphisms suggestive of Wolf-Hirschhorn syndrome.

April 14, 2015 - 8:37am
Related Articles

A case of 14q11.2 microdeletion with autistic features, severe obesity and facial dysmorphisms suggestive of Wolf-Hirschhorn syndrome.

Am J Med Genet A. 2014 Jan;164A(1):190-3

Authors: Terrone G, Cappuccio G, Genesio R, Esposito A, Fiorentino V, Riccitelli M, Nitsch L, Brunetti-Pierri N, Del Giudice E

Abstract
We report on a 21-year old woman with intellectual disability, autistic features, severe obesity, and facial dysmorphisms suggestive of Wolf-Hirschhorn syndrome (WHS). Array-CGH analysis showed a 2.89 Mb deletion on chromosome 14q11.2 containing 47 known genes. The most interesting genes included in this deletion are CHD8, a chromodomain helicase DNA binding protein that is associated with autism spectrum disorders, and MMP14, a matrix metalloproteinase that has been linked to obesity and type 2 diabetes. This report shows that 14q11.2 microdeletions can mimic WHS and suggests that gene(s) in the deleted interval that may be responsible for a phenocopy of WHS.

PMID: 24243641 [PubMed - indexed for MEDLINE]

Autistic spectrum disorders: A review of clinical features, theories and diagnosis.

April 12, 2015 - 6:28am

Autistic spectrum disorders: A review of clinical features, theories and diagnosis.

Int J Dev Neurosci. 2015 Apr 8;

Authors: Fakhoury M

Abstract
Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders that is among the most severe in terms of prevalence, morbidity and impact to the society. It is characterized by complex behavioral phenotype and deficits in both social and cognitive functions. Although the exact cause of ASD is still not known, the main findings emphasize the role of genetic and environmental factors in the development of autistic behavior. Environmental factors are also likely to interact with the genetic profile and cause aberrant changes in brain growth, neuronal development, and functional connectivity. The past few years have seen an increase in the prevalence of ASD, as a result of enhanced clinical tests and diagnostic tools. Despite growing evidence for the involvement of endogenous biomarkers in the pathophysiology of ASD, early detection of this disorder remains a big challenge. This paper describes the main behavioral and cognitive features of ASD, as well as the symptoms that differentiate autism from other developmental disorders. An attempt will be made to integrate all the available evidence which point to reduced brain connectivity, mirror neurons deficits, and inhibition-excitation imbalance in individuals with ASD. Finally, this review discusses the main factors involved in the pathophysiology of ASD, and illustrates some of the most important markers used for the diagnosis of this debilitating disorder.

PMID: 25862937 [PubMed - as supplied by publisher]

Phenotypic Association Analyses with Copy Number Variation in Recurrent Depressive Disorder.

April 12, 2015 - 6:28am

Phenotypic Association Analyses with Copy Number Variation in Recurrent Depressive Disorder.

Biol Psychiatry. 2015 Feb 25;

Authors: Rucker JJ, Tansey KE, Rivera M, Pinto D, Cohen-Woods S, Uher R, Aitchison KJ, Craddock N, Owen MJ, Jones L, Jones I, Korszun A, Barnes MR, Preisig M, Mors O, Maier W, Rice J, Rietschel M, Holsboer F, Farmer AE, Craig IW, Scherer SW, McGuffin P, Breen G

Abstract
BACKGROUND: Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD.
METHODS: In this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset.
RESULTS: We found an enrichment of Turner's syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79-33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002).
CONCLUSIONS: After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

PMID: 25861698 [PubMed - as supplied by publisher]

Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features.

April 11, 2015 - 8:35am

Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features.

Eur J Med Genet. 2015 Apr 6;

Authors: Fieremans N, Van Esch H, de Ravel T, Van Driessche J, Belet S, Bauters M, Froyen G

Abstract
Intellectual disability (ID) is a very heterogeneous disorder with over 100 ID genes located on the X chromosome alone. Of these, KDM5C and IQSEC2 are located adjacent to each other at the Xp11.22 locus. While mutations in either of these genes are associated with severe ID in males, female carriers are mostly unaffected. Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2. X-inactivation analysis revealed skewing in a lymphocyte-derived cell line from this patient with preferential inactivation of the mutant X chromosome. As the brain-expressed KDM5C and IQSEC2 genes escape X-inactivation, deletion of these alleles could still be detrimental despite skewing of X-inactivation. Indeed, mutations in either of both genes have been reported in a few female ID patients. Expression analysis in the patients' cell line revealed decreased KDM5C mRNA levels compared to female controls. IQSEC2 levels could not be compared due to very low expression in blood. Overall, our data suggest that heterozygous loss-of-function of the escape genes KDM5C and/or IQSEC2 can contribute to severe ID in female patients and should be taken into account in diagnostics.

PMID: 25858702 [PubMed - as supplied by publisher]

Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala.

April 11, 2015 - 8:35am
Related Articles

Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala.

J Neurophysiol. 2014 Aug 15;112(4):890-902

Authors: Martin BS, Corbin JG, Huntsman MM

Abstract
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability. Comorbidities of FXS such as autism are increasingly linked to imbalances in excitation and inhibition (E/I) as well as dysfunction in GABAergic transmission in a number of brain regions including the amygdala. However, the link between E/I imbalance and GABAergic transmission deficits in the FXS amygdala is poorly understood. Here we reveal that normal tonic GABAA receptor-mediated neurotransmission in principal neurons (PNs) of the basolateral amygdala (BLA) is comprised of both δ- and α5-subunit-containing GABAA receptors. Furthermore, tonic GABAergic capacity is reduced in these neurons in the Fmr1 knockout (KO) mouse model of FXS (1.5-fold total, 3-fold δ-subunit, and 2-fold α5-subunit mediated) as indicated by application of gabazine (50 μM), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 1 μM), and α5ia (1.5 μM) in whole cell patch-clamp recordings. Moreover, α5-containing tonic GABAA receptors appear to preferentially modulate nonsomatic compartments of BLA PNs. Examination of evoked feedforward synaptic transmission in these cells surprisingly revealed no differences in overall synaptic conductance or E/I balance between wild-type (WT) and Fmr1 KO mice. Instead, we observed altered feedforward kinetics in Fmr1 KO PNs that supports a subtle yet significant decrease in E/I balance at the peak of excitatory conductance. Blockade of α5-subunit-containing GABAA receptors replicated this condition in WT PNs. Therefore, our data suggest that tonic GABAA receptor-mediated neurotransmission can modulate synaptic E/I balance and timing established by feedforward inhibition and thus may represent a therapeutic target to enhance amygdala function in FXS.

PMID: 24848467 [PubMed - indexed for MEDLINE]

Language laterality, handedness and empathy in a sample of parents of children with autism spectrum disorder.

April 11, 2015 - 8:35am
Related Articles

Language laterality, handedness and empathy in a sample of parents of children with autism spectrum disorder.

Psicothema. 2014;26(1):17-20

Authors: Martínez-Sanchis S, Bernal Santacreu MC, Cortés Sancho R, Gadea Domenech M

Abstract
BACKGROUND: First-order relatives of persons with Autism Spectrum Disorder (ASD) exhibit a cognitive pattern which is part of a broader autism phenotype.
METHOD: The purpose of the present study was to evaluate whether some neuropsychological features related to the autism phenotype are present in parents of ASD children. To this end, the exploration included a dichotic listening task, handedness and the Empathy Quotient (EQ-60).
RESULTS: The scores obtained by the total sample (fathers plus mothers) were similar to those of the general population, although there were differences in some parameters of the dichotic listening task depending on the gender. Contrary to expectations, only in fathers, the negative correlation between data from both ears was not statistically significant, which could be evidence of a lack of hemispheric interdependence.
CONCLUSIONS: These results support the possible existence of a genetic susceptibility to an aberrant language asymmetry pattern. Moreover, possible unknown epigenetic factors could act on a vulnerable genotype in some ASD subjects. Nevertheless, due to the small sample size, the present research must be considered a pilot study.

PMID: 24444724 [PubMed - indexed for MEDLINE]

Age-dependent changes in the neural substrates of empathy in autism spectrum disorder.

April 11, 2015 - 8:35am
Related Articles

Age-dependent changes in the neural substrates of empathy in autism spectrum disorder.

Soc Cogn Affect Neurosci. 2014 Aug;9(8):1118-26

Authors: Schulte-Rüther M, Greimel E, Piefke M, Kamp-Becker I, Remschmidt H, Fink GR, Herpertz-Dahlmann B, Konrad K

Abstract
In typical development, empathic abilities continue to refine during adolescence and early adulthood. Children and adolescents with autism spectrum disorders (ASD) show deficits in empathy, whereas adults with ASD may have developed compensatory strategies. We aimed at comparing developmental trajectories in the neural mechanisms underlying empathy in individuals with ASD and typically developing control (TDC) subjects. Using an explicit empathizing paradigm and functional magnetic resonance imaging, 27 participants with ASD and 27 TDC aged 12-31 years were investigated. Participants were asked to empathize with emotional faces and to either infer the face's emotional state (other-task) or to judge their own emotional response (self-task). Differential age-dependent changes were evident during the self-task in the right dorsolateral prefrontal cortex, right medial prefrontal cortex, right inferior parietal cortex, right anterior insula and occipital cortex. Age-dependent decreases in neural activation in TDC were paralleled by either increasing or unchanged age-dependent activation in ASD. These data suggest ASD-associated deviations in the developmental trajectories of self-related processing during empathizing. In TDC, age-dependent modulations of brain areas may reflect the 'fine-tuning' of cortical networks by reduction of task-unspecific brain activity. Increased age-related activation in individuals with ASD may indicate the development of compensatory mechanisms.

PMID: 23784073 [PubMed - indexed for MEDLINE]

A de novo microdeletion of ANKRD11 gene in a Korean patient with KBG syndrome.

April 10, 2015 - 8:17am
Related Articles

A de novo microdeletion of ANKRD11 gene in a Korean patient with KBG syndrome.

Ann Lab Med. 2014 Sep;34(5):390-4

Authors: Lim JH, Seo EJ, Kim YM, Cho HJ, Lee JO, Cheon CK, Yoo HW

Abstract
KBG syndrome is a very rare genetic disorder characterized by macrodontia of upper central incisors, global developmental delay, distinctive craniofacial features, short stature, and skeletal anomalies. Ankyrin repeat domain 11 gene (ANKRD11) has recently been identified as a causal factor of this syndrome. We describe a 6-yr-old Korean boy with features of KBG syndrome. The patient had a short stature, macrodontia, dysmorphic facial features, speech and motor delay with intellectual disability, and partial seizures as indicated by the electroencephalogram, but he was neither autistic nor had autism spectrum disorders. Using high-resolution oligonucleotide array comparative genomic hybridization, we identified a heterozygous 240-kb deletion at 16q24.3 corresponding to ANKRD11. This patient provided additional evidence on the influence of ANKRD11 in KBG syndrome and suggested that deletion limited to ANKRD11 is unlikely to cause autism.

PMID: 25187894 [PubMed - indexed for MEDLINE]

Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism.

April 10, 2015 - 8:17am
Related Articles

Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism.

J Psychiatry Neurosci. 2014 Sep;39(5):294-303

Authors: Anitha A, Thanseem I, Nakamura K, Vasu MM, Yamada K, Ueki T, Iwayama Y, Toyota T, Tsuchiya KJ, Iwata Y, Suzuki K, Sugiyama T, Tsujii M, Yoshikawa T, Mori N

Abstract
BACKGROUND: In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism.
METHODS: We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition.
RESULTS: We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001).
LIMITATIONS: Study limitations include our small sample size of postmortem brains.
CONCLUSION: Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.

PMID: 24866414 [PubMed - indexed for MEDLINE]

Pages