Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53.

PLoS One. 2012;7(8):e42504

Authors: Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R, Giulivi C

Abstract
Etiology of aberrant social behavior consistently points to a strong polygenetic component involved in fundamental developmental pathways, with the potential of being enhanced by defects in bioenergetics. To this end, the occurrence of social deficits and mitochondrial outcomes were evaluated in conditional Pten (Phosphatase and tensin homolog) haplo-insufficient mice, in which only one allele was selectively knocked-out in neural tissues. Pten mutations have been linked to Alzheimer's disease and syndromic autism spectrum disorders, among others. By 4-6 weeks of age, Pten insufficiency resulted in the increase of several mitochondrial Complex activities (II-III, IV and V) not accompanied by increases in mitochondrial mass, consistent with an activation of the PI3K/Akt pathway, of which Pten is a negative modulator. At 8-13 weeks of age, Pten haplo-insufficient mice did not show significant behavioral abnormalities or changes in mitochondrial outcomes, but by 20-29 weeks, they displayed aberrant social behavior (social avoidance, failure to recognize familiar mouse, and repetitive self-grooming), macrocephaly, increased oxidative stress, decreased cytochrome c oxidase (CCO) activity (50%) and increased mtDNA deletions in cerebellum and hippocampus. Mitochondrial dysfunction was the result of a downregulation of p53-signaling pathway evaluated by lower protein expression of p21 (65% of controls) and the CCO chaperone SCO2 (47% of controls), two p53-downstream targets. This mechanism was confirmed in Pten-deficient striatal neurons and, HCT 116 cells with different p53 gene dosage. These results suggest a unique pathogenic mechanism of the Pten-p53 axis in mice with aberrant social behavior: loss of Pten (via p53) impairs mitochondrial function elicited by an early defective assembly of CCO and later enhanced by the accumulation of mtDNA deletions. Consistent with our results, (i) SCO2 deficiency and/or CCO activity defects have been reported in patients with learning disabilities including autism and (ii) mutated proteins in ASD have been found associated with p53-signaling pathways.

PMID: 22900024 [PubMed - indexed for MEDLINE]

Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice.

PLoS One. 2012;7(8):e42422

Authors: Bozdagi O, Sakurai T, Dorr N, Pilorge M, Takahashi N, Buxbaum JD

Abstract
BACKGROUND: Copy number variation (CNV) at the 15q11.2 region, which includes a gene that codes for CYFIP1 (cytoplasmic FMR1 interacting protein 1), has been implicated in autism, intellectual disability and additional neuropsychiatric phenotypes. In the current study we studied the function of Cyfip1 in synaptic physiology and behavior, using mice with a disruption of the Cyfip1 gene.
METHODOLOGY/PRINCIPAL FINDINGS: We observed that in Cyfip1 heterozygous mice metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) induced by paired-pulse low frequency stimulation (PP-LFS) was significantly increased in comparison to wildtype mice. In addition, mGluR-LTD was not affected in the presence of protein synthesis inhibitor in the Cyfip1 heterozygous mice, while the same treatment inhibited LTD in wildtype littermate controls. mGluR-agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD was also significantly increased in hippocampal slices from Cyfip1 heterozygous mice and again showed independence from protein synthesis only in the heterozygous animals. Furthermore, we observed that the mammalian Target of Rapamycin (mTOR) inhibitor rapamycin was only effective at reducing mGluR-LTD in wildtype animals. Behaviorally, Cyfip1 heterozygous mice showed enhanced extinction of inhibitory avoidance. Application of both mGluR5 and mGluR1 antagonist to slices from Cyfip1 heterozygous mice reversed the increase in DHPG-induced LTD in these mice.
CONCLUSIONS/SIGNIFICANCE: These results demonstrate that haploinsufficiency of Cyfip1 mimics key aspects of the phenotype of Fmr1 knockout mice and are consistent with the hypothesis that these effects are mediated by interaction of Cyfip1 and Fmrp in regulating activity-dependent translation. The data provide support for a model where CYFIP1 haploinsufficiency in patients results in intermediate phenotypes increasing risk for neuropsychiatric disorders.

PMID: 22900020 [PubMed - indexed for MEDLINE]

[Family paracentric inversion of the short arm of chromosome X (Xp21.2p11.23) and connection with autism spectrum disorders].

Srp Arh Celok Lek. 2012 Nov-Dec;140(11-12):760-4

Authors: Milovančević MP, Vešić M, Jelisavčić M, Nikšić S, Pilić GR, Maravić VM

Abstract
INTRODUCTION: Autism spectrum disorders (ASDs) are a group of complex pervasive developmental disorders characterized by impairments in communication, social interaction and behavior. In most cases autism is caused by a combination of genetic factors and environmental risk factors. In 10% to 20% of cases it has been shown that the cause of ASD is genetic.
CASE OUTLINE: We are describing a 2-year-old boy who was referred to genetic counseling because of speech delay and certain autism-like behavior. By cytogenetic analysis the karyotype 46, inv(X),Y was obtained. The boy was a carrier of a paracentric inversion of the short arm of the chromosome X. After cytogenetic analysis of parental blood, it was detected that mother was a carrier of identical aberration, but had no clinical signs. The method of fluorescent in situ hybridization (FISH) yielded the precise breakpoint in the region (p21.2p11.23). Mother and son were carriers of identical X chromosome.
CONCLUSION: Breakpoints are located in the regions that have already been linked to autism, which indicates that the positional effect of the gene could have been a possible cause of the patient's genotype. In addition to positional effects, in order to better understand the etiology of autism other genetic and environmental factors should be always taken into consideration.

PMID: 23350252 [PubMed - indexed for MEDLINE]

Moderating effects of autism on parent views of genetic screening for aggression.

Intellect Dev Disabil. 2012 Oct;50(5):415-25

Authors: May ME, Brandt RC, Bohannan JK

Abstract
Advances in gene-environment interaction research have revealed genes that are associated with aggression. However, little is known about parent perceptions of genetic screening for behavioral symptoms like aggression as opposed to diagnosing disabilities. These perceptions may influence future research endeavors involving genetic linkage studies to behavior, including proactive approaches for parents to avoid events leading to aggression. The purpose of this study was to solicit the perspectives of parents who have children with autism about screening for genes associated with aggression, compared to responses from those who have children without disabilities and those planning to have children. Parents of children with autism were more likely to support screening and the use of the results to seek treatment if necessary. Results are discussed in the context of surveillance screening and systematic early intervention for behavioral symptoms related to autism. The results may provide insight for clincians, researchers, policymakers, and advocacy groups related to diagnosing and treating aggression in people with autism.

PMID: 23025643 [PubMed - indexed for MEDLINE]

CNVs leading to fusion transcripts in individuals with autism spectrum disorder.

Eur J Hum Genet. 2012 Nov;20(11):1141-7

Authors: Holt R, Sykes NH, Conceição IC, Cazier JB, Anney RJ, Oliveira G, Gallagher L, Vicente A, Monaco AP, Pagnamenta AT

Abstract
There is strong evidence that rare copy number variants (CNVs) have a role in susceptibility to autism spectrum disorders (ASDs). Much research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels. We investigated an alternative mechanism whereby CNVs combine the 5' and 3' ends of two genes, creating a 'fusion gene'. Any resulting mRNA with an open reading frame could potentially alter the phenotype via a gain-of-function mechanism. We examined 2382 and 3096 rare CNVs from 996 individuals with ASD and 1287 controls, respectively, for potential to generate fusion transcripts. There was no increased burden in individuals with ASD; 122/996 cases harbored at least one rare CNV of this type, compared with 179/1287 controls (P=0.89). There was also no difference in the overall frequency distribution between cases and controls. We examined specific examples of such CNVs nominated by case-control analysis and a candidate approach. Accordingly, a duplication involving REEP1-POLR1A (found in 3/996 cases and 0/1287 controls) and a single occurrence CNV involving KIAA0319-TDP2 were tested. However, no fusion transcripts were detected by RT-PCR. Analysis of additional samples based on cell line availability resulted in validation of a MAPKAPK5-ACAD10 fusion transcript in two probands. However, this variant was present in controls at a similar rate and is unlikely to influence ASD susceptibility. In summary, although we find no evidence that fusion-gene generating CNVs lead to ASD susceptibility, discovery of a MAPKAPK5-ACAD10 transcript with an estimated frequency of ~1/200 suggests that gain-of-function mechanisms should be considered in future CNVs studies.

PMID: 22549408 [PubMed - indexed for MEDLINE]

Genetic testing for autism spectrum disorders.

Dev Disabil Res Rev. 2011;17(1):3-8

Authors: Bauer SC, Msall ME

Abstract
Children with autism spectrum disorders (ASD) have unique developmental and behavioral phenotypes, and they have specific challenges with communication, social skills, and repetitive behaviors. At this time, no single etiology for ASD has been identified. However, evidence from family studies and linkage analyses suggests that genetic factors play a pivotal role in the etiology of ASD. However, ASD appear to be influenced by complex genetic and environmental factors, and evidence suggests that this is not a single gene disorder. In particular, ASD has a complex behavioral phenotype, and this variation reflects complex genotypes under the influence of external factors. With these considerations in mind, it is important to recognize that genetic testing is a vital component of the diagnostic evaluation of children with ASD. For example, children with ASD who have definitive etiologies may be able to access more specific resources, they may be spared long, emotionally and financially exhausting diagnostic journeys, and associated medical conditions and comorbidities can be managed proactively. Most importantly, children with disabilities of unknown origin should have an ongoing evaluation of potential etiologies for their symptoms (Crocker, 1987). Our purpose is to describe current trends in genetic testing for ASD, potential genetic etiologies of ASD, known genetic disorders associated with ASD, and recommendations for genetic testing in ASD. We will also emphasize the importance of access to informed health professionals, especially in the contexts of stigma and community supports.

PMID: 22447748 [PubMed - indexed for MEDLINE]

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486.

Proc Natl Acad Sci U S A. 2013 Mar 18;

Authors: Dolan BM, Duron SG, Campbell DA, Vollrath B, Rao BS, Ko HY, Lin GG, Govindarajan A, Choi SY, Tonegawa S

Abstract
Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition-including hyperactivity, repetitive behaviors, and seizures-as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor-which we call FRAX486-also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.

PMID: 23509247 [PubMed - as supplied by publisher]

Investigation of the Mitochondrial ATPase 6/8 and tRNA(Lys) Genes Mutations in Autism.

Cell J. 2012;14(2):98-101

Authors: Piryaei F, Houshmand M, Aryani O, Dadgar S, Soheili ZS

Abstract
OBJECTIVE: Autism results from developmental factors that affect many or all functional brain systems. Brain is one of tissues which are crucially in need of adenosine triphosphate (ATP). Autism is noticeably affected by mitochondrial dysfunction which impairs energy metabolism. Considering mutations within ATPase 6, ATPase 8 and tRNA(Lys) genes, associated with different neural diseases, and the main role of ATPase 6/8 in energy generation, we decided to investigate mutations on these mtDNA-encoded genes to reveal their roles in autism pathogenesis.
MATERIALS AND METHODS: In this experimental study, mutation analysis for the mentioned genes were performed in a cohort of 24 unrelated patients with idiopathic autism by employing amplicon sequencing of mtDNA fragments.
RESULTS: In this study, 12 patients (50%) showed point mutations that represent a significant correlation between autism and mtDNA variations. Most of the identified substitutions (55.55%) were observed on MT-ATP6, altering some conserved amino acids to other ones which could potentially affect ATPase 6 function. Mutations causing amino acid replacement denote involvement of mtDNA genes, especially ATPase 6 in autism pathogenesis.
CONCLUSION: MtDNA mutations in relation with autism could be remarkable to realize an understandable mechanism of pathogenesis in order to achieve therapeutic solutions.

PMID: 23508290 [PubMed - as supplied by publisher]

Genomic and epigenomic insights into nutrition and brain disorders.

Nutrients. 2013;5(3):887-914

Authors: Dauncey MJ

Abstract
Considerable evidence links many neuropsychiatric, neurodevelopmental and neurodegenerative disorders with multiple complex interactions between genetics and environmental factors such as nutrition. Mental health problems, autism, eating disorders, Alzheimer's disease, schizophrenia, Parkinson's disease and brain tumours are related to individual variability in numerous protein-coding and non-coding regions of the genome. However, genotype does not necessarily determine neurological phenotype because the epigenome modulates gene expression in response to endogenous and exogenous regulators, throughout the life-cycle. Studies using both genome-wide analysis of multiple genes and comprehensive analysis of specific genes are providing new insights into genetic and epigenetic mechanisms underlying nutrition and neuroscience. This review provides a critical evaluation of the following related areas: (1) recent advances in genomic and epigenomic technologies, and their relevance to brain disorders; (2) the emerging role of non-coding RNAs as key regulators of transcription, epigenetic processes and gene silencing; (3) novel approaches to nutrition, epigenetics and neuroscience; (4) gene-environment interactions, especially in the serotonergic system, as a paradigm of the multiple signalling pathways affected in neuropsychiatric and neurological disorders. Current and future advances in these four areas should contribute significantly to the prevention, amelioration and treatment of multiple devastating brain disorders.

PMID: 23503168 [PubMed - in process]

Genome-wide sequencing for the identification of rearrangements associated with Tourette syndrome and obsessive-compulsive disorder.

BMC Med Genet. 2012;13:123

Authors: Hooper SD, Johansson AC, Tellgren-Roth C, Stattin EL, Dahl N, Cavelier L, Feuk L

Abstract
BACKGROUND: Tourette Syndrome (TS) is a neuropsychiatric disorder in children characterized by motor and verbal tics. Although several genes have been suggested in the etiology of TS, the genetic mechanisms remain poorly understood.
METHODS: Using cytogenetics and FISH analysis, we identified an apparently balanced t(6,22)(q16.2;p13) in a male patient with TS and obsessive-compulsive disorder (OCD). In order to map the breakpoints and to identify additional submicroscopic rearrangements, we performed whole genome mate-pair sequencing and CGH-array analysis on DNA from the proband.
RESULTS: Sequence and CGH array analysis revealed a 400 kb deletion located 1.3 Mb telomeric of the chromosome 6q breakpoint, which has not been reported in controls. The deletion affects three genes (GPR63, NDUFA4 and KLHL32) and overlaps a region previously found deleted in a girl with autistic features and speech delay. The proband's mother, also a carrier of the translocation, was diagnosed with OCD and shares the deletion. We also describe a further potentially related rearrangement which, while unmapped in Homo sapiens, was consistent with the chimpanzee genome.
CONCLUSIONS: We conclude that genome-wide sequencing at relatively low resolution can be used for the identification of submicroscopic rearrangements. We also show that large rearrangements may escape detection using standard analysis of whole genome sequencing data. Our findings further provide a candidate region for TS and OCD on chromosome 6q16.

PMID: 23253088 [PubMed - indexed for MEDLINE]

Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings.

JAMA Psychiatry. 2013 Jan;70(1):22-30

Authors: Power RA, Kyaga S, Uher R, MacCabe JH, Långström N, Landen M, McGuffin P, Lewis CM, Lichtenstein P, Svensson AC

Abstract
CONTEXT: It is unknown how genetic variants conferring liability to psychiatric disorders survive in the population despite strong negative selection. However, this is key to understanding their etiology and designing studies to identify risk variants.
OBJECTIVES: To examine the reproductive fitness of patients with schizophrenia and other psychiatric disorders vs their unaffected siblings and to evaluate the level of selection on causal genetic variants.
DESIGN: We measured the fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse and their unaffected siblings compared with the general population.
SETTING: Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register.
PARTICIPANTS: In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden.
MAIN OUTCOME MEASURES: Fertility ratio (FR), reflecting the mean number of children compared with that of the general population, accounting for age, sex, family size, and affected status.
RESULTS: Except for women with depression, affected patients had significantly fewer children (FR range for those with psychiatric disorder, 0.23-0.93; P < 10-10). This reduction was consistently greater among men than women, suggesting that male fitness was particularly sensitive. Although sisters of patients with schizophrenia and bipolar disorder had increased fecundity (FR range, 1.02-1.03; P < .01), this was too small on its own to counterbalance the reduced fitness of affected patients. Brothers of patients with schizophrenia and autism showed reduced fecundity (FR range, 0.94-0.97; P < .001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; P < 10-10). In the case of depression, this more than compensated for the lower fecundity of affected individuals.
CONCLUSIONS: Our results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism. Bipolar disorder did not seem to be under strong negative selection. Vulnerability to depression, and perhaps substance abuse, may be preserved by balancing selection, suggesting the involvement of common genetic variants in ways that depend on other genes and on environment.

PMID: 23147713 [PubMed - indexed for MEDLINE]

A prospective study of autistic-like traits in unaffected siblings of probands with autism spectrum disorder.

JAMA Psychiatry. 2013 Jan;70(1):42-8

Authors: Georgiades S, Szatmari P, Zwaigenbaum L, Bryson S, Brian J, Roberts W, Smith I, Vaillancourt T, Roncadin C, Garon N

Abstract
CONTEXT: The presence of autistic-like traits in relatives of individuals with autism spectrum disorder (ASD) is well recognized, but, to our knowledge, the emergence of these traits early in development has not been studied.
OBJECTIVE: To prospectively investigate the emergence of autistic-like traits in unaffected (no ASD diagnosis) infant siblings of probands diagnosed as having ASD.
DESIGN: Two groups of children unaffected with ASD were assessed prospectively-siblings of probands diagnosed as having ASD (high risk [HR]) and control subjects with no family history of ASD (low risk [LR]). Scores on a measure of autistic-like traits at 12 months of age were used in a cluster analysis of the entire sample.
SETTING: A prospective study of infant siblings of probands with ASD from 3 diagnostic centers in Canada.
PARTICIPANTS: The study included 170 HR and 90 LR children, none of whom was diagnosed as having ASD at age 3 years.
MAIN OUTCOME MEASURES: The Autism Observation Scale for Infants was used to measure autistic-like traits and derive clusters at 12 months of age. Clusters were compared on ASD symptoms, cognitive abilities, and social-emotional difficulties at age 3 years.
RESULTS: Two clusters were identified. Cluster 1 (n = 37; 14.2% of total sample) had significantly higher levels of autistic-like traits compared with cluster 2. Within cluster 1, 33 children came from the siblings (19.4% of HR group) and only 4 came from the control subjects (4.5% of LR group). At age 3 years, children from cluster 1 had more social-communication impairment (effect size > 0.70; P < .001), lower cognitive abilities (effect size = -0.59; P < .005), and more internalizing problems (effect size = 0.55; P = .01). Compared with control subjects, HR siblings had a relative risk of 4.3 (95% CI,1.6-11.9) for membership in cluster 1.
CONCLUSIONS: Study findings suggest the emergence of autistic-like traits resembling a broader autism phenotype by 12 months of age in approximately 19% of HR siblings who did not meet ASD diagnostic criteria at age 3 years.

PMID: 22945359 [PubMed - indexed for MEDLINE]

Association study of genes regulating opioid system in autism.

Psychiatry Res. 2012 Jun 30;198(1):169-70

Authors: Čupić B, Hranilovic D, Jernej B, Gabrilovac J

PMID: 22382050 [PubMed - indexed for MEDLINE]

An unbalanced translocation involving loss of 10q26.2 and gain of 11q25 in a pedigree with autism spectrum disorder and cerebellar juvenile pilocytic astrocytoma.

Am J Med Genet A. 2013 Mar 12;

Authors: Minhas HM, Pescosolido MF, Schwede M, Piasecka J, Gaitanis J, Tantravahi U, Morrow EM

Abstract
We report on a pedigree with a pair of brothers each with minor anomalies, developmental delay, and autistic-symptoms who share an unbalanced translocation (not detectable by karyotype). The unbalanced translocation involves a 7.1 Mb loss of the terminal portion of 10q, and a 4.2 Mb gain of 11q. One of the brothers also developed a cerebellar juvenile pilocytic astrocytoma. The father was found to be a balanced carrier and the couple had a previous miscarriage. We demonstrate that the breakpoint for the triplicated region from chromosome 11 is adjacent to two IgLON genes, namely Neurotrimin (NTM) and Opioid Binding Protein/Cell Adhesion Molecule-like (OPCML). These genes are highly similar neural cell adhesion molecules that have been implicated in synaptogenesis and oncogenesis, respectively. The children also have a 10q deletion and are compared to other children with the 10q deletion syndrome which generally does not involve autism spectrum disorders (ASDs) or cancer. Together these data support a role for NTM and OPCML in developmental delay and potentially in cancer susceptibility. © 2013 Wiley Periodicals, Inc.

PMID: 23495067 [PubMed - as supplied by publisher]

Partial deletion of ANKRD11 results in the KBG phenotype distinct from the 16q24.3 microdeletion syndrome.

Am J Med Genet A. 2013 Mar 12;

Authors: Khalifa M, Stein J, Grau L, Nelson V, Meck J, Aradhya S, Duby J

Abstract
KBG syndrome (OMIM 148050) is a very rare genetic disorder characterized by macrodontia, distinctive craniofacial abnormalities, short stature, intellectual disability, skeletal, and neurologic involvement. Approximately 60 patients have been reported since it was first described in 1975. Recently mutations in ANKRD11 have been documented in patients with KBG syndrome, and it has been proposed that haploinsufficiency of ANKRD11 is the cause of this syndrome. In addition, copy number variation in the 16q24.3 region that includes ANKRD11 results in a variable phenotype that overlaps with KBG syndrome and also includes autism spectrum disorders and other dysmorphic facial features. In this report we present a 2½-year-old African American male with features highly suggestive of KBG syndrome. Genomic microarray identified an intragenic 154 kb deletion at 16q24.3 within ANKRD11. This child's mother was mosaic for the same deletion (present in approximately 38% of cells) and exhibited a milder phenotype including macrodontia, short stature and brachydactyly. This family provides additional evidence that ANKRD11 causes KBG syndrome, and the mild phenotype in the mosaic form suggests that KBG phenotypes might be dose dependent, differentiating it from the more variable 16q24.3 microdeletion syndrome. This family has additional features that might expand the phenotype of KBG syndrome. © 2013 Wiley Periodicals, Inc.

PMID: 23494856 [PubMed - as supplied by publisher]

Modeling socially anhedonic syndromes: genetic and pharmacological manipulation of opioid neurotransmission in mice.

Transl Psychiatry. 2012;2:e155

Authors: Cinque C, Pondiki S, Oddi D, Di Certo MG, Marinelli S, Troisi A, Moles A, D'Amato FR

Abstract
Social anhedonia, or the diminished capacity to experience pleasure and reward from social affiliation, is a major symptom of different psychiatric disorders, including some forms of infantile autism and schizophrenia spectrum disorders. The brain opioid hypothesis of social attachment is a promising model for achieving insights into how neurobiological and developmental factors contribute to the regulation of social reward. In this study, genetic knocking-out and naltrexone (NTRX) treatment during the first 4 days of life were used to disrupt opioid neurotransmission in mouse pups and their attachment relationships with the mother. Both permanent (genetic) and transient (pharmacological) manipulations of opioid neurotransmission exerted long-term effects on social affiliation. When juveniles, both μ-opioid receptor knockout mice and NTRX-treated pups showed reduced interest in peers and no preference for socially rewarding environment. These results demonstrate that sociability in juvenile mice is highly dependent on the establishment during infancy of a positive affective relationship with their mothers and that opioid neurotransmission has a major role in the regulation of social hedonic capacity. If the validity of this animal model will be confirmed by future research, translational studies focusing on the interaction between early experience and opioid neurotransmission could provide useful insights for identifying endophenotypes of human psychiatric disorders associated with social anhedonia.

PMID: 22929597 [PubMed - indexed for MEDLINE]

Dosage effects of X and Y chromosomes on language and social functioning in children with supernumerary sex chromosome aneuploidies: implications for idiopathic language impairment and autism spectrum disorders.

J Child Psychol Psychiatry. 2012 Oct;53(10):1072-81

Authors: Lee NR, Wallace GL, Adeyemi EI, Lopez KC, Blumenthal JD, Clasen LS, Giedd JN

Abstract
BACKGROUND:  Supernumerary sex chromosome aneuploidies (X/Y-aneuploidies), the presence of extra X and/or Y chromosomes, are associated with heightened rates of language impairments and social difficulties. However, no single study has examined different language domains and social functioning in the same sample of children with tri-, tetra-, and pentasomy X/Y-aneuploidy. The current research sought to fill this gap in the literature and to examine dosage effects of X and Y chromosomes on language and social functioning.
METHODS: Participants included 110 youth with X/Y-aneuploidies (32 female) and 52 with typical development (25 female) matched on age (mean ∼12 years; range 4-22) and maternal education. Participants completed the Wechsler intelligence scales, and parents completed the children's communication checklist-2 and the social responsiveness scale to assess language skills and autistic traits, respectively.
RESULTS: Both supernumerary X and Y chromosomes were related to depressed structural and pragmatic language skills and increased autistic traits. The addition of a Y chromosome had a disproportionately greater impact on pragmatic language; the addition of one or more X chromosomes had a disproportionately greater impact on structural language.
CONCLUSIONS: Given that we link extra X chromosomes with structural language impairments and an extra Y chromosome with pragmatic language impairments, X/Y-aneuploidies may provide clues to genetic mechanisms contributing to idiopathic language impairment and autism spectrum disorders.

PMID: 22827287 [PubMed - indexed for MEDLINE]

GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.

Transl Psychiatry. 2012;2:e142

Authors: Gandal MJ, Sisti J, Klook K, Ortinski PI, Leitman V, Liang Y, Thieu T, Anderson R, Pierce RC, Jonak G, Gur RE, Carlson G, Siegel SJ

Abstract
Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30-80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory-inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1(neo-/-) mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABA(B)-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.

PMID: 22806213 [PubMed - indexed for MEDLINE]

Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder.

Hum Mol Genet. 2012 Oct 1;21(19):4356-64

Authors: Mondal K, Ramachandran D, Patel VC, Hagen KR, Bose P, Cutler DJ, Zwick ME

Abstract
Autism spectrum disorder (ASD) is a heterogeneous disorder with substantial heritability, most of which is unexplained. ASD has a population prevalence of one percent and affects four times as many males as females. Patients with fragile X E (FRAXE) intellectual disability, which is caused by a silencing of the X-linked gene AFF2, display a number of ASD-like phenotypes. Duplications and deletions at the AFF2 locus have also been reported in cases with moderate intellectual disability and ASD. We hypothesized that other rare X-linked sequence variants at the AFF2 locus might contribute to ASD. We sequenced the AFF2 genomic region in 202 male ASD probands and found that 2.5% of males sequenced had missense mutations at highly conserved evolutionary sites. When compared with the frequency of missense mutations in 5545 X chromosomes from unaffected controls, we saw a statistically significant enrichment in patients with ASD (OR: 4.9; P < 0.014). In addition, we identified rare AFF2 3' UTR variants at conserved sites which alter gene expression in a luciferase assay. These data suggest that rare variation in AFF2 may be a previously unrecognized ASD susceptibility locus and may help explain some of the male excess of ASD.

PMID: 22773736 [PubMed - indexed for MEDLINE]

RBFOX1 regulates both splicing and transcriptional networks in human neuronal development.

Hum Mol Genet. 2012 Oct 1;21(19):4171-86

Authors: Fogel BL, Wexler E, Wahnich A, Friedrich T, Vijayendran C, Gao F, Parikshak N, Konopka G, Geschwind DH

Abstract
RNA splicing plays a critical role in the programming of neuronal differentiation and, consequently, normal human neurodevelopment, and its disruption may underlie neurodevelopmental and neuropsychiatric disorders. The RNA-binding protein, fox-1 homolog (RBFOX1; also termed A2BP1 or FOX1), is a neuron-specific splicing factor predicted to regulate neuronal splicing networks clinically implicated in neurodevelopmental disease, including autism spectrum disorder (ASD), but only a few targets have been experimentally identified. We used RNA sequencing to identify the RBFOX1 splicing network at a genome-wide level in primary human neural stem cells during differentiation. We observe that RBFOX1 regulates a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. Downstream alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. Several of these differentially expressed genes are further implicated in ASD and related neurodevelopmental diseases. Weighted gene co-expression network analysis demonstrates a high degree of connectivity among these disease-related genes, highlighting RBFOX1 as a key factor coordinating the regulation of both neurodevelopmentally important alternative splicing events and clinically relevant neuronal transcriptional programs in the development of human neurons.

PMID: 22730494 [PubMed - indexed for MEDLINE]