Cortical Serotonin Type-2 Receptor Density in Parents of Children with Autism Spectrum Disorders
Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada.Journal of Autism and Developmental Disorders (Impact Factor: 3.34). 08/2008; 39(1):97-104. DOI: 10.1007/s10803-008-0604-4
Parents (N = 19) of children with autism spectrum disorders (ASD) and adult controls (N = 17) underwent positron emission tomography (PET) using [(18)F]setoperone to image cortical serotonin type-2 (5-HT2) receptors. The 5-HT2 binding potentials (BPs) were calculated by ratioing [(18)F]setoperone intensity in regions of interest (ROI) to cerebellar intensity. Cortical 5-HT2 BPs were significantly lower in parents compared to controls and platelet 5-HT levels were significantly negatively correlated with cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents of children with ASD is consistent with reports of diminished 5-HT2 expression and functioning in individuals with ASD. Further research should examine the relationship of reduced 5-HT2 receptor expression to underlying causation and to clinical and neurochemical correlates of autistic behavior.
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- "First, atypical antipsychotics, acting via HTR2A, are known to alleviate repetitive behaviour and aggression in ASD patients [Buitelaar & Willemsen-Swinkels, 2000; Marek, Carpenter, McDougle, & Price, 2003]. Furthermore, ASD subjects or their relatives displayed significant reduction in cortical [Goldberg et al., 2009; Murphy et al., 2006; Oblak, Gibbs, & Blatt, 2013] as well as platelet [Cook et al., 1993; McBride et al., 1989] HTR2A binding. Also, platelet aggregation, an indirect measure of platelet HTR2A activity/number, was found to be reduced in ASD subjects [Hranilovic et al., 2009; McBride et al., 1989; Safai-Kutti, Denfors, Kutti, & Wadenvik, 1988]. "
ABSTRACT: Disturbed brain and peripheral serotonin homeostasis is often found in subjects with autism spectrum disorder (ASD). The role of the serotonin receptor 2A (HTR2A) in the regulation of central and peripheral serotonin homeostasis, as well as its altered expression in autistic subjects, have implicated the HTR2A gene as a major candidate for the serotonin disturbance seen in autism. Several studies, yielding so far inconclusive results, have attempted to associate autism with a functional SNP -1438 G/A (rs6311) in the HTR2A promoter region, while possible contribution of epigenetic mechanisms, such as DNA methylation, to HTR2A dysregulation in autism has not yet been investigated. In this study, we compared the mean DNA methylation within the regulatory region of the HTR2A gene between autistic and control subjects. DNA methylation was analysed in peripheral blood leukocytes using bisulfite conversion and sequencing of the HTR2A region containing rs6311 polymorphism. Autistic subjects of rs6311 AG genotype displayed higher mean methylation levels within the analysed region than the corresponding controls (P < 0.05), while there was no statistically significant difference for AA and GG carriers. Our study provides preliminary evidence for increased HTR2A promoter methylation in leukocytes of a portion of adult autistic subjects, indicating that epigenetic mechanisms might contribute to HTR2A dysregulation observed in individuals with ASD. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
- "Nakamura et al.  used PET imaging and found reduced 5-HT transporter (5-HTT) binding in the anterior and posterior cingulate cortices associated with impairment in social cognition in individuals with high functioning autism and reduction of 5-HTT binding in the thalamus correlated to obsessive behaviors and interests. Goldberg et al.  published findings from a PET imaging study on the parents of children with Autism Spectrum Disorders (ASD) having significantly reduced 5-HT2 binding and found that their platelet 5-HT levels were inversely correlated to the 5-HT2 binding potential. "
Article: The Neuropathology of Autism[Show abstract] [Hide abstract]
ABSTRACT: Autism is a behaviorally defined neurodevelopmental disorder that affects over 1% of new births in the United States and about 2% of boys. The etiologies are unknown and they are genetically complex. There may be epigenetic effects, environmental influences, and other factors that contribute to the mechanisms and affected neural pathway(s). The underlying neuropathology of the disorder has been evolving in the literature to include specific brain areas in the cerebellum, limbic system, and cortex. Part(s) of structures appear to be affected most rather than the entire structure, for example, select nuclei of the amygdala, the fusiform face area, and so forth. Altered cortical organization characterized by more frequent and narrower minicolumns and early overgrowth of the frontal portion of the brain, affects connectivity. Abnormalities include cytoarchitectonic laminar differences, excess white matter neurons, decreased numbers of GABAergic cerebellar Purkinje cells, and other events that can be traced developmentally and cause anomalies in circuitry. Problems with neurotransmission are evident by recent receptor and binding site studies especially in the inhibitory GABA system likely contributing to an imbalance of excitatory/inhibitory transmission. As postmortem findings are related to core behavior symptoms, and technology improves, researchers are gaining a much better perspective of contributing factors to the disorder.
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- "Other studies have evaluated 5-HT receptor binding. Two neuroimaging studies have found decreased 5-HT2 receptor binding, one a SPECT study in adults with Asperger’s syndrome  and the second a PET study in parents of children with autism . Blatt’s group has also presented data demonstrating decreased 5-HT2A binding in post-mortem samples from autism subjects . "
ABSTRACT: Alterations in peripheral and central indices of serotonin (5-hydroxytryptamine, 5-HT) production, storage and signaling have long been associated with autism. The 5-HT transporter gene (HTT, SERT, SLC6A4) has received considerable attention as a potential risk locus for autism-spectrum disorders, as well as disorders with overlapping symptoms, including obsessive-compulsive disorder (OCD). Here, we review our efforts to characterize rare, nonsynonymous polymorphisms in SERT derived from multiplex pedigrees carrying diagnoses of autism and OCD and present the initial stages of our effort to model one of these variants, Gly56Ala, in vivo. We generated a targeting vector to produce the Gly56Ala substitution in the Slc6a4 locus by homologous recombination. Following removal of a neomycin resistance selection cassette, animals exhibiting germline transmission of the Ala56 variant were bred to establish a breeding colony on a 129S6 background, suitable for initial evaluation of biochemical, physiological and behavioral alterations relative to SERT Gly56 (wild-type) animals. SERT Ala56 mice were achieved and exhibit a normal pattern of transmission. The initial growth and gross morphology of these animals is comparable to wildtype littermate controls. The SERT Ala56 variant can be propagated in 129S6 mice without apparent disruption of fertility and growth. We discuss both the opportunities and challenges that await the physiological/behavioral analysis of Gly56Ala transgenic mice, with particular reference to modeling autism-associated traits.