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)

The substrate-binding sites in membrane transporters are alternately accessible from either side of the membrane, but the molecular basis of how this alternate opening of internal and external gates is achieved is largely unknown. Here we present data indicating that, in the neuronal electrogenic sodium- and potassium-coupled glutamate transporter EAAC-1, the substrate-binding site and one of the gates, or a residue controlling the gating process, are in close physical proximity. Arginine 445, located only two residues away from a residue implicated in glutamate binding (Bendahan, A., Armon, A., Madani, N., Kavanaugh, M. P., and Kanner, B. I. (2000) J. Biol. Chem. 275, 37436-37442), has been mutated to serine (R445S). Upon expression in oocytes, measurements of l-[(3)H]-glutamate transport under voltage clamp reveal that the charge/flux ratio for l-glutamate at -60 mV is approximately 30-fold higher than that of the wild type. Also, with d-aspartate, R445S exhibits an approximately 15-fold increase in this ratio. In contrast to the wild type, the reversal potential of the substrate-dependent currents in R445S shifts to more negative potentials when either the external sodium or potassium concentration is decreased. These findings indicate that these two cations are the main current carriers in the R445S mutant. Introduction of a methionine or a glutamine, but not a lysine, at position 445 gives rise to a phenotype similar to R445S. Therefore, it seems that the elimination of a positive charge in the vicinity of the substrate-binding site converts the transporter into a glutamate-gated cation-conducting pathway.
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PMID:Arginine 445 controls the coupling between glutamate and cations in the neuronal transporter EAAC-1. 1459 97

Rett syndrome is characterized by disruption of a period of vigorous brain growth with synapse development. Neurotrophic factors are important regulators of neuronal growth, differentiation, and survival during early brain development. The aims of this study were to study the role of neurotrophic factors in Rett syndrome, specifically whether Rett syndrome has abnormal levels of specific neurotrophic factors in serum and cerebrospinal fluid and whether the changes differ from other neuropediatric patients, for example, those with infantile autism. Four neurotrophic factors were measured: nerve growth factor, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1 from the frozen cerebrospinal fluid and from serum (except glial cell line-derived neurotrophic factor) by enzyme-linked immunosorbent assay and cerebrospinal fluid glutamate and aspartate by high-performance liquid chromatography (HPLC) method in patients with Rett syndrome. Insulin-like growth factor 1 was measured from the cerebrospinal fluid of patients with infantile autism. We found low concentrations of cerebrospinal fluid nerve growth factor in patients with Rett syndrome compared with control patients. The serum levels and other cerebrospinal fluid neurotrophic factor levels of the patients did not differ from the controls. Patients with Rett syndrome had high cerebrospinal fluid glutamate levels. Patients with infantile autism had low cerebrospinal fluid insulin-like growth factor 1 levels. Nerve growth factor acts especially on cholinergic neurons of the basal forebrain, whereas insulin-like growth factor 1 acts on cerebellar neurons. In Rett syndrome, the forebrain is more severely affected than the other cortical areas. In autism, many studies show hippocampal or cerebellar pathology. Our findings are in agreement with the different morphologic and neurochemical findings (brain growth, affected brain areas, neurotransmitter metabolism) in the two syndromes. Impairment in dendritic development in Rett syndrome could be the consequence of cholinergic deficiency and of neurotrophic factor/glutamate imbalance. Cholinergic gene expression might be influenced by the Rett syndrome gene directly or via the neurotrophic factor system.
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PMID:Neurotrophic factors in the pathogenesis of Rett syndrome. 1464 51

The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.
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PMID:Neurotoxic effects of postnatal thimerosal are mouse strain dependent. 1518 8

In 1998, Horvath et al. (1998) observed a marked improvement in speech, eye contact, and attention in autistic children five weeks after treatment with secretin, which ocurred in the course of an endoscopic investigation. Since autism is hypothesized to be a hypoglutamatergic disorder we investigated the in vivo effects of secretin on extracellular amino acids in the rat brain. Studies were carried out on freely moving rats with microdialysis probes in the hippocampus. Amino acids were examined using tandem mass spectroscopy and HPLC/fluorometric detection. Following secretin injection (8.7 microg/kg i.p.), considerable increases in microdialysate glutamate and gamma-aminobutyric acid (GABA) levels were observed; other amino acids were not affected. The observed increased microdialysate concentrations of glutamate and GABA following secretin application may explain the results of the Horvath study.
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PMID:Effects of secretin on extracellular amino acid concentrations in rat hippocampus. 1520 7

Many of the diverse functional consequences of activating group 1 metabotropic glutamate receptors require translation of pre-existing mRNA near synapses. One of these consequences is long-term depression (LTD) of transmission at hippocampal synapses. Loss of fragile X mental retardation protein (FMRP), the defect responsible for fragile X syndrome in humans, increases LTD in mouse hippocampus. This finding is consistent with the growing evidence that FMRP normally functions as a repressor of translation of specific mRNAs. Here we present a theory that can account for diverse neurological and psychiatric aspects of fragile X syndrome, based on the assumption that many of the protein-synthesis-dependent functions of metabotropic receptors are exaggerated in fragile X syndrome. The theory suggests new directions for basic research as well as novel therapeutic approaches for the treatment of humans with fragile X, the most frequent inherited cause of mental retardation and an identified cause of autism.
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PMID:The mGluR theory of fragile X mental retardation. 1521 35

The glutamate pathways are involved in diverse processes such as learning and memory, epilepsy, and they play important roles in neural plasticity, neural development, and neurodegeneration. It has been proposed that autism could be a hypoglutamatergic disorder. Recently, Jamain et al. reported that the glutamate receptor 6 (GluR6 or GRIK2) is in linkage disequilibrium with autism. In the present study, the transmission disequilibrium test (TDT) and the haplotype transmission were performed to analyze the four SNPs (SNP1: rs995640; SNP2: rs2227281; SNP3: rs2227283; SNP4: rs2235076) of GluR6 in 174 Chinese Han parent-offspring trios. The TDT demonstrated that the two SNPs (SNP2 and SNP3) showed preferential transmission (TDT P = 0.032). The global chi(2) test for haplotype transmission also revealed an association between GluR6 and autism (chi(2) = 10.78, df = 3, P = 0.013). Our results suggested that GluR6 is in linkage disequilibrium with autism.
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PMID:Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios. 1538 69

Recent studies have revealed that the pituitary adenylate cyclase-activating polypeptide (PACAP) might act as a psychostimulant. Here we investigated the mechanisms underlying motor hyperactivity in patients with pervasive developmental disorders, such as autism, and attention-deficit hyperactivity disorder (ADHD). We studied the effects of intracisternal administration of 6-hydroxydopamine (6-OHDA) or endocrine disruptors (EDs) on spontaneous motor activity (SMA) and multiple gene expression in neonatal rats. Treatment with 6-OHDA caused significant hyperactivity during the dark phase in rats aged 4-5 weeks. Motor hyperactivities also were observed after treatment with endocrine disruptors, such as bisphenol A, nonylphenol, diethylhexyl phthalate and dibutyl phthalate, during both dark and light phases. Gene-expression profiles produced using cDNA macroarrays of 8-week-old rats with 6-OHDA lesions revealed the altered expression of several classes of gene, including the N-methyl-D-aspartate (NMDA) receptor 1, glutamate/aspartate transporter, gamma-aminobutyric-acid transporter, dopamine transporter 1, D4 receptor, and peptidergic elements such as the galanin receptor, arginine vasopressin receptor, neuropeptide Y and tachykinin 2. The changes in gene expression caused by treatment with endocrine disruptors differed from those induced by 6-OHDA. These results suggest that the mechanisms underlying the induction of motor hyperactivity and/or compensatory changes in young adult rats might differ between 6-OHDA and endocrine disruptors.
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PMID:Motor hyperactivity caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: a study inspired by the physiological roles of PACAP in the brain. 1551 16

Serotonin (5-hydroxytryptamine, 5-HT) is an amine neurotransmitter derived from tryptophan and is important in brain systems regulating mood, emotional behavior, and sleep. Selective serotonin reuptake inhibitor (SSRI) drugs are used to treat disorders such as depression, stress, eating disorders, autism, and schizophrenia. It is thought that these drugs act to prolong the action of 5-HT by blocking reuptake. This may lead to decreased 5-HT content in the nerve fibers themselves; however, this has not previously been directly demonstrated. We have studied the effects of administration of two drugs, imipramine and citalopram, on levels of 5-HT in nerve fibers in the murine brain. Quantitative analysis of the areal density of 5-HT fibers throughout the brain was performed using ImageJ software. While a high density of fibers was observed in mid- and hind-brain regions and areas such as thalamus and hypothalamus, densities were far lower in areas such as cortex, where SSRIs might be thought to exert their actions. As anticipated, imipramine and citalopram produced a decline in 5-HT levels in nerve fibers, but the result was not uniform. Areas such as inferior colliculus showed significant reduction whereas little, if any, change was observed in the adjacent superior colliculus. The reason for, and significance of, this regionality is unclear. It has been proposed that serotonin effects in the brain might be linked to changes in glutamatergic transmission. Extracellular glutamate levels are regulated primarily by glial glutamate transporters. Qualitative evaluation of glutamate transporter immunolabeling in cortex of control and drug-treated mice revealed no discernable difference in intensity of glutamate transporter immunoreactivity. These data suggest that changes in intracellular and extracellular levels of serotonin do not cause concomitant changes in astroglial glutamate transporter expression, and thus cannot represent a mechanism for the delayed efficacy of antidepressants when administered clinically.
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PMID:Quantitative analysis of immunolabeling for serotonin and for glutamate transporters after administration of imipramine and citalopram. 1585 94

Review of neurochemical investigations in autistic disorder revealed that a wide array of transmitter systems have been studied, including serotonin, dopamine, norepinephrine, acetylcholine, oxytocin, endogenous opioids, cortisol, glutamate, and gamma-aminobutyric acid (GABA). These studies have been complicated by the fact that autism is a very heterogeneous disorder which often presents with comorbid behavioral problems. In addition, many of these studies employed very small samples and inappropriate control groups, making it difficult to draw conclusions with confidence. Overall, serotonin appears to have the most empirical evidence for a role in autism, but this requires further investigation and replication. There is little support for the notion that a dysfunction of norepinephrine or the endogenous opioids are related to autism. The role of dopaminergic functioning has not been compelling thus far, though conflicting findings on central dopamine turnover require further study. Promising new areas of study may include possible dysfunction of the cholinergic system, oxytocin, and amino acid neurotransmitters. Implications for pharmacotherapy are briefly discussed for each neurotransmitter system with brief research examples. Review of this work emphasizes the need for future studies to control for subject variables, such as race, sex, pubertal status, and distress associated with blood draws, which can affect measures of neurochemical function. In addition, research in neurochemistry must continue to work in concert with other subspecialties to form a more comprehensive and theory-based approach to the neurobiological correlates of autistic disorder.
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PMID:Neurochemical correlates of autistic disorder: a review of the literature. 1600 61

Dopamine (DA) acts as a key neurotransmitter in the brain. Numerous studies have shown its regulatory role in motor and cognitive function. However, the impairment of emotional processes in neurologic and psychiatric pathologies involving the dopaminergic system (Parkinson disease, schizophrenia, autism, Attention Deficit Hyperactivity Disorder, Huntington disease, frontal lobe lesions), as well as the influence that administration of dopaminergic agonists/antagonists exert on the processing of emotion, suggest a role for DA in emotional processes. Moreover, emotional processes are dependent upon a variety of structures, the majority of which form part of the limbic system and are subject to DA innervation. In reviewing the literature, the amygdala emerges as a brain structure critical for emotional processing. It may also be implicated in deficits in emotional recognition found in two major disorders where DA's implication is clear: Parkinson disease and schizophrenia. In addition, the amygdala's response to emotional tasks is likely to be altered by the administration of both agonist and antagonist dopaminergic drugs. Experimental studies reinforce the idea of a dopaminergic contribution to emotional response, as suggested by biochemical, pharmacologic, and lesion experiments. Although the implication of the dopaminergic system in emotional processing appears to be clearly documented, the contribution of specific DA receptor subtypes, or of the DA cotransmitters cholecystokinin and neurotensin, or even glutamate, is, however, still unclear. Altogether, these observations suggest that DA has, undoubtedly, a direct and/or indirect role in the full emotional process.
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PMID:Dopaminergic contribution to the regulation of emotional perception. 1623 63


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