Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Enhanced activity of human serotonin transporter variants associated with autism. 1895 75

Attention deficit/hyperactivity disorder (AD/HD) is a heterogeneous developmental disorder with an etiology that is not fully understood. AD/HD has been considered to occur due to a disturbance in cathecholaminergic neurotransmission, with particular emphasis on dopamine. The neurotransmission of dopamine in subcortical regions such as the basal ganglia and limbic areas is synaptic; on the other hand, dopamine neurotransmission in the frontal cortex is quite different, because there are very few dopamine transporters (DAT) in the frontal cortex that allow dopamine to diffuse away from the dopamine synapse ("volume transmission"). It is now clear that noradrenergic neurons play a key regulatory role in dopaminergic function in the frontal cortex. Furthermore, serotonergic neurons exert an inhibitory effect on midbrain dopamine cell bodies, and they have an influence on dopamine release in terminal regions. There is accumulating neurobiological evidence pointing toward a role of the serotonin system in AD/HD. The etiology of autism spectrum disorders (ASD) is still unclear, but information from genetics, neuropathology, brain imaging, and basic neuroscience has provided insights into the understanding of this developmental disorder. In addition to abnormal circuitry in specific limbic and neocortical areas of the cerebral cortex, impairments in brainstem, cerebellar, thalamic, and basal ganglia connections have been reported. Numerous studies have pointed to abnormalities in serotonin and glutamate neurotransmission. Three important aspects involved in the pathophysiology of ASD have been proposed. The first is cell migration, the second is unbalanced excitatory-inhibitory networks, and the third is synapse formation and pruning, the key factors being reelin, neurexin, and neuroligin. Serotonin is considered to play an important role in all of these aspects of the pathophysiology of ASD. Finally, I would like to emphasize that it is crucial in the field of child neurology medical examination and treatment should be based on the basic neuroscience, always taking "neurons" into consideration.
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PMID:[Neurotransmission in developmental disorders]. 1903 85

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J x DBA/2J = BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.
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PMID:Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes. 1917 83

The oxytocin receptor has been implicated in the regulation of reproductive physiology as well as social and emotional behaviors. The neurochemical mechanisms by which oxytocin receptor modulates social and emotional behavior remains elusive, in part because of a lack of sensitive and selective antibodies for cellular localization. To more precisely characterize oxytocin receptor-expressing neurons within the brain, we generated an oxytocin receptor-reporter mouse in which part of the oxytocin receptor gene was replaced with Venus cDNA (a variant of yellow fluorescent protein). Examination of the Venus expression revealed that, in the raphe nuclei, about one-half of tryptophan hydroxylase-immunoreactive neurons were positive for Venus, suggesting a potential role for oxytocin in the modulation of serotonin release. Oxytocin infusion facilitated serotonin release within the median raphe nucleus and reduced anxiety-related behavior. Infusion of a 5-HT(2A/2C) receptor antagonist blocked the anxiolytic effect of oxytocin, suggesting that oxytocin receptor activation in serotonergic neurons mediates the anxiolytic effects of oxytocin. This is the first demonstration that oxytocin may regulate serotonin release and exert anxiolytic effects via direct activation of oxytocin receptor expressed in serotonergic neurons of the raphe nuclei. These results also have important implications for psychiatric disorders such as autism and depression in which both the oxytocin and serotonin systems have been implicated.
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PMID:Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. 1922 79

Prenatal exposure to chemicals is well known to induce developmental abnormalities in the central nervous system of children. Developmental neurotoxicity (DNT) tests are important to identify neurotoxic agents and prevent neurodevelopmental disorders. We have investigated DNT, focusing on the fetal brain shortly after chemical exposure. To demonstrate a usefulness of a study focusing on the fetal brain in DNT tests, we assessed the fetal brain in a rat valproate-induced autism model. Rats were treated with sodium valproate (VPA, 800 mg/kg) orally on gestational day (GD) 9 or 11 (VPA9 or VPA11), and the fetal brains were examined on GD16 using immunohistochemistry for serotonin (5-HT), tyrosine hydroxylase (TH), and TuJ1 (neuron specific class III beta-tubulin). Hypoplasia of the cortical plate was induced in both VPA9 and VPA11 groups. Abnormal migration of TH-positive and 5-HT neurons, possibly due to the appearance of an abnormally running nerve tract in the pons, was observed only in the VPA11 group. In addition, when we compared the incidence of these abnormalities between pregnant rats mated in our own animal facility (in-house group), and rats purchased pregnant (supplier group), the supplier group was much more sensitive, especially to the pons abnormality. Shipping stress may affect the reproducibility of VPA-induced DNT. The present results demonstrate that examination of the GD16 fetal brain was useful for detecting and characterizing abnormal development of the brain after VPA exposure. Further discussion was made with reference to the findings in children with autism.
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PMID:Observation of fetal brain in a rat valproate-induced autism model: a developmental neurotoxicity study. 1946 Jun 35

The role of fibroblast growth factor receptors (FGFR) in normal brain development has been well-documented in transgenic and knock-out mouse models. Changes in FGF and its receptors have also been observed in schizophrenia and related developmental disorders. The current study examines a transgenic th(tk-)/th(tk-) mouse model with FGF receptor signaling disruption targeted to dopamine (DA) neurons, resulting in neurodevelopmental, anatomical, and biochemical alterations similar to those observed in human schizophrenia. We show in th(tk-)/th(tk-) mice that hypoplastic development of DA systems induces serotonergic hyperinnervation of midbrain DA nuclei, demonstrating the co-developmental relationship between DA and 5-HT systems. Behaviorally, th(tk-)/th(tk-) mice displayed impaired sensory gaiting and reduced social interactions correctable by atypical antipsychotics (AAPD) and a specific 5-HT2A antagonist, M100907. The adult onset of neurochemical and behavioral deficits was consistent with the postpubertal time course of psychotic symptoms in schizophrenia and related disorders. The spectrum of abnormalities observed in th(tk-)/th(tk-) mice and the ability of AAPD to correct the behavioral deficits consistent with human psychosis suggests that midbrain 5-HT2A-controlling systems are important loci of therapeutic action. These results may provide further insight into the complex multi-neurotransmitter etiology of neurodevelopmental diseases such autism, bipolar disorder, Asperger's Syndrome and schizophrenia.
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PMID:Serotonergic hyperinnervation and effective serotonin blockade in an FGF receptor developmental model of psychosis. 1957 Jun 52

Serotonin (5-HT) is involved in many developmental processes and influences behaviors including anxiety, aggression, and cognition. Disruption of the serotonergic system has been implicated in human disorders including autism, depression, schizophrenia, and ADHD. Although pharmacological, neurotoxin, and dietary manipulation of 5-HT and tryptophan hydroxylase has added to our understanding of the serotonergic system, the results are complicated by multiple factors. A newly identified ETS domain transcription factor, Pet-1, has direct control of major aspects of 5-HT neuronal development. Pet-1 is the only known factor that is restricted in the brain to 5-HT neurons during development and adulthood and exerts dominant control over 5-HT neuronal phenotype. Disruption of Pet-1 produces an approximately 80% loss of 5-HT neurons and content and results in increased aggression in male Pet-1(-/-) mice [Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES (2003) Neuron 37:233-247]. We hypothesized that Pet-1(-/-) mice would also exhibit changes in anxiety and cognition. Pet-1(-/-) mice were hypoactive which may have affected the observed lack of anxious behavior in the elevated zero maze and light-dark test. Pet-1(-/-) mice, however, were more defensive during marble burying and showed acoustic startle hyper-reactivity. No deficits in spatial, egocentric, or novel object recognition learning were found in Pet-1(-/-) mice. These findings were unexpected given that 5-HT depleting drugs given to adult or developing animals result in learning deficits [Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997) Brain Res 760:68-73; Morford LL, Inman-Wood SL, Gudelsky GA, Williams MT, Vorhees CV (2002) Eur J Neurosci 16:491-500; Vorhees CV, Schaefer TL, Williams MT (2007) Synapse 61:488-499]. Lack of differences may be the result of compensatory mechanisms in reaction to a constitutive knock out of Pet-1 or 5-HT may not be as important in learning and memory as previously suspected.
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PMID:Mouse plasmacytoma-expressed transcript 1 knock out induced 5-HT disruption results in a lack of cognitive deficits and an anxiety phenotype complicated by hypoactivity and defensiveness. 1978 75

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.
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PMID:Modeling rare gene variation to gain insight into the oldest biomarker in autism: construction of the serotonin transporter Gly56Ala knock-in mouse. 1996 97

A single systemic administration of serotonin (5-HT) antibodies on day-1 of the life of rat has been investigated for neurotransmitter contents in nucleus raphe, and several discrete brain regions, as well as for serotoninergic syndromes and nociceptive responses in adult animals. 5-HT antiserum raised in rabbits were purified and characterized prior to subcutaneous administration in neonatal rats. Control animals received normal rabbit serum. Antibodies tagged with radioactive iodine were traced in the brains of rat pups treated subcutaneously. These animals at adulthood, exhibited an increase in body weight, increased sensitivity to serotonin agonist 5-methoxy-N-N-dimethyl tryptamine, and to nociceptive stimulus to subcutaneously administered formalin. Animals neonatally treated with 5-HT antiserum once on day 1 of life, exhibited significant decrease in the contents of serotonin and its metabolite as compared to normal serum treated animals specifically in nucleus raphe dorsalis, but not in substantia gresia centralis, nucleus accumbens, nucleus caudatus putamen, substantia nigra or tuberculum olfactorium during the study period of seven days to four months. The contents of dopamine or norepinephrine were not consistently altered in any of the nuclei studied. Since 5-HT is known to act as a trophic factor for its own development and its target areas, exposure to 5-HT antibodies during birth might have adversely affected the development of the serotoninergic system and resulted in long-lasting changes in behavior and 5-HT levels in the brain. These results have strong implications for the treatment of childhood developmental disorders such as autism where hyperserotoninemia is associated with the disease syndromes.
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PMID:Early-life treatment of antiserotonin antibodies alters sensitivity to serotonin receptors, nociceptive stimulus and serotonin metabolism in adult rats. 2018 13

Serotonin transporter clustering is an important feature for regulation of this transporter activity. We used immunocytochemistry to analyze alterations in serotonin transporter clustering in blood lymphocytes of reeler mice. Serotonin transporter immunolabelling is observed mostly as a patchy staining in lymphocytes membranes. Comparison of the number and size of serotonin transporter clusters in wild-type mice, heterozygous reeler mice, and homozygous reeler mice showed an increase in the number and size of clusters in heterozygous reeler mice, but only an increase in clusters size in homozygous reeler mice. Reelin is down-regulated in the brain of schizophrenia, autism, and mood disorders, and is also expressed in blood plasma. There is the possibility therefore that alterations in serotonin transporter clustering in blood lymphocytes associated with a decrease in reelin expression may be operative in some cardiovascular or immune system alterations showing comorbidity with these mental disorders.
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PMID:Serotonin transporter clustering in blood lymphocytes of reeler mice. 2041 72


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