Cerebral Cortical Gray Matter Overgrowth and Functional Variation of the Serotonin Transporter Gene in Autism

Wassink, Thomas H.; Hazlett, Heather C.; Epping, Eric A.; Arndt, Stephan; Dager, Stephen R.; Schellenberg, Gerard D.; Dawson, Geraldine; Piven, Joseph

doi:10.1001/archpsyc.64.6.709

Cited by 93 publications

(67 citation statements)

References 76 publications

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“…Rodent studies demonstrate a significant effect on brain structure (Persico et al 2003;Altamura et al 2007) and behaviour (Holmes et al 2002(Holmes et al , 2003 following genetic or pharmacological manipulations of SERTand/ or 5-HT during development (Whitaker-Azmitia et al 1996;Bengel et al 1998). In this regard, recent studies examining a common SERT promoter polymorphism (5HTTLPR) have linked autism-associated changes Autism-associated SERT coding variants H. C. Prasad et al 169 in brain size to altered SERT expression (Wassink et al 2007). Possibly, the gain of function changes in SERT activity could be compounded by the purportedly higher functioning l/l genotype of the 5HTTLPR.…”

Section: Discussionmentioning

confidence: 99%

Enhanced activity of human serotonin transporter variants associated with autism

Prasad

Steiner

Sutcliffe

et al. 2008

Phil. Trans. R. Soc. B

119

111

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Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling. Here, we document functional perturbations of three of these variants: Ile425Leu; Phe465Leu; and Leu550Val. In transiently transfected HeLa cells, the three variants confer a gain of 5-HT transport phenotype. Specifically, enhanced SERT activity was also observed in lymphoblastoid lines derived from mutation carriers. In contrast to previously characterized Gly56Ala, where increased transport activity derives from catalytic activation, the three novel variants exhibit elevated surface density as revealed through both surface antagonist-binding and biotinylation studies. Unlike Gly56Ala, mutants Ile425Leu, Phe465Leu and Leu550Val retain a capacity for acute PKG and p38 MAPK regulation. However, both Gly56Ala and Ile425Leu demonstrate markedly reduced sensitivity to PP2A antagonists, suggesting that deficits in trafficking and catalytic modulation may derive from a common basis in perturbed phosphatase regulation. When expressed stably from the same genomic locus in CHO cells, both Gly56Ala and Ile425Leu display catalytic activation, accompanied by a striking loss of SERT protein.

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Section: Discussionmentioning

confidence: 99%

Enhanced activity of human serotonin transporter variants associated with autism

Prasad

Steiner

Sutcliffe

et al. 2008

Phil. Trans. R. Soc. B

119

111

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“…5-HTTLPR polymorphism has been shown to influence the cerebral cortical gray matter volumes in 44 male children (2-4 years old) with autism. The S allele was linked with increasing gray matter volume (Wassink et al 2007). The genotypespecific phenotypes for 5-HTTLPR have also been linked to the variation in specific symptoms in individuals with autism (Brune et al 2006).…”

Section: Control 68mentioning

confidence: 99%

5-HTTLPR Polymorphism: Analysis in South African Autistic Individuals

et al. 2010

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“…The range of defining and associated features includes reduced eye contact, lack of gesturing, language delays, lack of prosody in speech, inability to interpret emotions from the facial expressions of others, reduced joint attention, impaired attentional shift, hypersensitivity to sensory stimuli, stereotyped hand flapping and upset to change in routine (9,17,53,54,61,66,100,118,182). Additional associated features in some cases include mental retardation, absence of Theory of Mind, seizures, self-injury, anxiety, sleep disturbances, gastrointestinal disturbances and larger head circumference and brain volume at young ages (2,51,52,54,66,74,78,140,153,167,182,187). The importance of genetic factors in the etiology of autism is recognized in the growing literature of twin and family studies that demonstrate up to 60% concordance for autism and 90% concordance for autism spectrum disorders between monozygotic twins, as well as a male : female ratio of approximately 4:1 (13,52,64).…”

mentioning

confidence: 99%

Mouse Behavioral Assays Relevant to the Symptoms of Autism*

2007

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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. Pathol 2007;17:448-459. Brain STRATEGIES FOR DESIGNING MOUSE MODELS OF AUTISMDeveloping rodent behavioral tasks relevant to the symptoms of autism presents a unique challenge to behavioral neuroscientists. Rodent models of neuropsychiatric disorders have a long and illustrious history. Models of generalized anxiety disorder have focused on approach-avoidance conflict behaviors, including the elevated plus maze, light↔dark exploration, marble burying and Vogel thirsty-lick conflict tests (19, 35, 41, 44,60,62,88,163,172). Cognitive deficits in Alzheimer's models are detected with learning and memory tests, including (i) spatial navigation tasks such as the Morris water maze, Barnes maze, radial maze and T-maze; (ii) working memor...

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Cerebral Cortical Gray Matter Overgrowth and Functional Variation of the Serotonin Transporter Gene in Autism

Abstract: The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism.

Cited by 93 publications

References 76 publications

Enhanced activity of human serotonin transporter variants associated with autism

Enhanced activity of human serotonin transporter variants associated with autism

5-HTTLPR Polymorphism: Analysis in South African Autistic Individuals

Mouse Behavioral Assays Relevant to the Symptoms of Autism*

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