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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a male child with autism found to have maternal uniparental disomy (UPD) of chromosome 1. The child met diagnostic criteria for the three symptom domains of autism: language impairment, deficient social communication and excessively rigid and repetitive behaviours. He also had a variety of features often associated with autism, including mild mental retardation, small head circumference, hyperactivity, poor fine motor skills, slightly dysmorphic facial features and a heightened interest in olfactory stimulation. His brother, who did not have chromosome 1 UPD, was also autistic. The mother, but not the father, had a history of psychiatric illness and a number of personality and social traits similar to the core features of autism. The discovery of the cytogenetic abnormality was made during the course of a genome-wide linkage screen, wherein genotypes at 6 out of 17 chromosome 1 markers were non-Mendelian and all transmissions were consistent with UPD. Further genotyping (a total of 54 markers) revealed alternating regions of heterodisomy and isodisomy. Whereas chromosome 1 UPD has not been shown to cause disease by effects on imprinting, numerous reports exist of the abnormality unmasking recessive disease-causing mutations. In agreement with this, one of the regions of isodisomy overlaps an emerging chromosome 1 region of interest in autism located at 150-160 Mb.
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PMID:A case of autism and uniparental disomy of chromosome 1. 1588

Pathological changes in neuronal density in the amygdaloid complex have been associated with various neurological disorders. However, due to variable shrinkage during tissue processing, the only way to determine changes in neuron number unambiguously is to estimate absolute counts, rather than neuronal density. As the first stage in evaluating potential neuropathology of the amygdala in autism, the total number of neurons was estimated in the control human amygdaloid complex by using stereological sampling. The intact amygdaloid complex from one hemisphere of 10 brains was frozen and sectioned. One 100-microm section was selected every 500 microm and stained by the standard Nissl method. The entire amygdaloid complex was outlined and then further partitioned into five reliably defined subdivisions: 1) the lateral nucleus, 2) the basal nucleus, 3) the accessory basal nucleus, 4) the central nucleus, and 5) the remaining nuclei (including anterior cortical, anterior amygdaloid area, periamygdaloid cortex, medial, posterior cortical, nucleus of the lateral olfactory tract, amygdalohippocampal area, and intercalated nuclei). The number of neurons was measured by using an optical fractionator with Stereoinvestigator software. The mean number of neurons (x 10(6)) for each region was as follows: lateral nucleus 4.00, basal nucleus 3.24, accessory basal nucleus 1.28, central nucleus 0.36, remaining nuclei 3.33, and total amygdaloid complex 12.21. The stereological assessment of neuron number in the human amygdala provides an essential baseline for comparison of patient populations, such as autism, in which the amygdala may develop abnormally. To facilitate these types of analyses, this paper provides a detailed anatomical description of the methods used to define subdivisions of the human amygdaloid complex.
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PMID:Stereological estimation of the number of neurons in the human amygdaloid complex. 1617 50

Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the vasopressin 1A receptor (V1A), can stimulate aggressive behavior. Using a novel monocylic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed with high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a resident-intruder model of offensive aggression. Resident, male Syrian golden hamsters were given oral doses of SRX251 or intraperitoneal Manning compound, a selective V1a receptor antagonist with reduced brain penetrance, at doses of 0.2 microg, 20 microg, 2 mg/kg or vehicle. When tested 90-120 min later, SRX251, but not Manning compound, caused a significant dose-dependent reduction in offensive aggression toward intruders as measured by latency to bite and number of bites. The reduction in aggression persisted for over 6 h and was no longer present 12 h post treatment. SRX251 did not alter the amount of time the resident investigated the intruder, olfactory communication, general motor activity, or sexual motivation. These data corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse.
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PMID:Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior. 1650 76

Oxytocin mediates social affiliation behaviors and social memory in rodents. It has been suggested that disruptions in oxytocin contribute to the deficits in reciprocal social interactions that characterize autism. The present experiments employed a new social approach task for mice which is designed to detect low levels of sociability, representing the first diagnostic criterion for autism. Two lines of oxytocin knockout mice were tested, the National Institute of Mental Health line in Bethesda, and the Baylor/Emory line at the University of North Carolina in Chapel Hill. Similar methods were used for each line to evaluate tendencies to spend time with a stranger mouse versus with an inanimate novel object with no social valence. Adult C57BL/6J males were tested identically, as controls to confirm the robustness of the methods used in the social task. Comprehensive phenotyping of general health, neurological reflexes, olfactory and other sensory abilities, and motor functions was employed to assess both lines. No genotype differences were detected in any of the control measures for either line. Normal sociability, measured as time spent with a novel stranger mouse as compared to time spent with a novel object, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls. Normal preference for social novelty, measured as time spent with a second novel stranger as compared to time spent with a more familiar mouse, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls, with minor exceptions. Similar behavioral results from two independent targeted gene mutations, generated with different targeting vectors, bred on different genetic backgrounds, and tested in different laboratory environments, corroborates the negative findings on sociability in oxytocin mutant mice. Intact tendencies to spend time with another mouse versus with a novel object, in both lines of oxytocin knockouts, supports an interpretation that oxytocin plays a highly specific role in social memory, but is not essential for general spontaneous social approach in mice.
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PMID:Social approach behaviors in oxytocin knockout mice: comparison of two independent lines tested in different laboratory environments. 1742 46

Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self-grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety-like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3-hydroxylase, an enzyme-regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism-like behavioral phenotypes. Robust and selective social deficits, repetitive self-grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.
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PMID:Autism-like behavioral phenotypes in BTBR T+tf/J mice. 1755 18

While the cause of autism remains unknown, the high concordance between monozygotic twins supports a strong genetic component. The importance of genetic factors in autism encourages the development of mutant mouse models, to advance our understanding of biological mechanisms underlying autistic behaviors. Mouse models of human neuropsychiatric diseases are designed to optimize (i) face validity (resemblance to the human symptoms) (ii) construct validity (similarity to the underlying causes of the disease) and (iii) predictive validity (expected responses to treatments that are effective in the human disease). There is a growing need for mouse behavioral tasks with all three types of validity, to define robust phenotypes in mouse models of autism. Ideal mouse models will incorporate analogies to the three diagnostic symptoms of autism: abnormal social interactions, deficits in communication and high levels of repetitive behaviors. Social approach is tested in an automated three chambered apparatus that offers the subject a choice between spending time with another mouse, with a novel object, or remaining in an empty familiar environment. Reciprocal social interaction is scored from videotapes of interactions between pairs of unfamiliar mice. Communication is evaluated by measuring emission and responses to vocalizations and olfactory cues. Repetitive behaviors are scored for measures of grooming, jumping, or stereotyped sniffing of one location or object. Insistence on sameness is modeled by scoring a change in habit, for example, reversal of the spatial location of a reinforcer in the Morris water maze or T-maze. Associated features of autism, for example, mouse phenotypes relevant to anxiety, seizures, sleep disturbances and sensory hypersensitivity, may be useful to include in a mouse model that meets some of the core diagnostic criteria. Applications of these assays include (i) behavioral phenotyping of transgenic and knockout mice with mutations in genes relevant to autism; (ii) characterization of inbred strains of mice; (iii) evaluation of environmental toxins; (iv) comparison of behavioral phenotypes with genetic factors, such as unusual expression patterns of genes or unusual single nucleotide polymorphisms; and (v) evaluation of proposed therapeutics for the treatment of autism.
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PMID:Mouse behavioral assays relevant to the symptoms of autism. 1791 30

Prior research has reliably found high blood (hyperserotonemia) - but low brain - serotonin levels in autistic individuals. At early stages of development, high levels of serotonin in the blood may enter the brain of a developing fetus, causing a loss of serotonin terminals through negative feedback and thus disrupting subsequent serotonergic function. The current study extends earlier findings in a developmental hyperserotonemia (DHS) model of autism in Sprague-Dawley rats by treating 8 dams of developing rat pups with a serotonergic agonist, 5-methoxytryptamine (5-MT; 1 mg/kg) during development (from gestational day 12 to post-natal day 20; PND 20). DHS pups exhibited post-injection seizures, which were non-existent in saline-treated pups (p<0.05). Behavioral results in infancy indicated that DHS pups spent less time with the dam during the active phase on PNDs 15-17 (p<0.05) and experienced decreased maternal bonding in a return to dam task on PND 17 (p<0.05). On subsequent tests, DHS animals exhibited greater gnawing reactions to a novel stimulus (p<0.05), less behavioral inhibition (p<0.05), and had fewer olfactory-based social interactions (p<0.05) and greater non-olfactory mounting (p<0.05). However, there were no changes in anxiogenic behavior using the elevated plus maze (p>0.05). Post mortem analyses revealed that DHS animals had a loss of oxytocin (OT)-containing cells in the paraventricular nucleus in the hypothalamus (PVN; p<0.05) as well as an increase in calcitonin-gene related peptide (CGRP; p<0.05, one tailed) processes in the central nucleus of the amygdala (CeA) on PND 198. These results may correspond to hypothalamic and amygdalar changes in the human condition and suggest that the hyperserotonemia model of autism may be a valid model which produces many of the social, behavioral, and peptide changes inherent to autism.
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PMID:Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes. 1806 43

Repetitive behavior, a core symptom of autism, encompasses stereotyped responses, restricted interests, and resistance to change. These studies investigated whether different components of the repetitive behavior domain could be modeled in the exploratory hole-board task in mice. Four inbred mouse strains, C57BL/6J, BALB/cByJ, BTBR T+tf/J, and FVB/NJ, and mice with reduced expression of Grin1, leading to NMDA receptor hypofunction (NR1neo/neo mice), were tested for exploration and preference for olfactory stimuli in an activity chamber with a 16-hole floor-board. Reduced exploration and high preference for holes located in the corners of the chamber were observed in BALB/cByJ and BTBR T+tf/J mice. All inbred strains had initial high preference for a familiar olfactory stimulus (clean cage bedding). BTBR T+tf/J was the only strain that did not demonstrate a shift in hole preference towards an appetitive olfactory stimulus (cereal or a chocolate chip), following home cage exposure to the food. The NR1neo/neo mice showed lower hole selectivity and aberrant olfactory stimulus preference, in comparison to wildtype controls. The results indicate that NR1neo/neo mice have repetitive nose poke responses that are less modified by environmental contingencies than responses in wildtype mice. 25-30% of NMDA receptor hypomorphic mice also show self-injurious responses. Findings from the olfactory studies suggest that resistance to change and restricted interests might be modeled in mice by a failure to alter patterns of hole preference following familiarization with an appetitive stimulus, and by high preference persistently demonstrated for one particular olfactory stimulus. Further work is required to determine the characteristics of optimal mouse social stimuli in the olfactory hole-board test.
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PMID:Development of a mouse test for repetitive, restricted behaviors: relevance to autism. 1806 25

Mouse models for the study of autistic-like behaviors are increasingly needed to test hypotheses about the causes of autism, and to evaluate potential treatments. Both the automated three-chambered social approach test and social transmission of food preference have been proposed as mouse behavioral assays with face validity to diagnostic symptoms of autism, including aberrant reciprocal social interactions and impaired communication. Both assays measure aspects of normal social behavior in the mouse. However, little is known regarding the salient cues present in each assay that elicit normal social approach and communication. To deconstruct the critical components, we focused on delivering discrete social and non-social olfactory and visual cues within the context of each assay. Results indicate that social olfactory cues were sufficient to elicit normal sociability in the three-chambered social approach test. On social transmission of food preference, isolated social olfactory cues were sufficient to induce social investigation, but not sufficient to induce food preference. These findings indicate that olfactory cues are important in mouse social interaction, but that additional sensory cues are necessary in certain situations. The present evidence that both the three-chambered social approach assay and the social transmission of food preference assay require socially relevant cues to elicit normal behavior supports the use of these two assays to investigate autism-related behavioral phenotypes in mice.
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PMID:Olfactory cues are sufficient to elicit social approach behaviors but not social transmission of food preference in C57BL/6J mice. 1858 54

Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations.
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PMID:Identification of Arx transcriptional targets in the developing basal forebrain. 1879 76


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