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Acid Decarboxylase (acid + decarboxylase)
Kinds of Acid Decarboxylase Selected AbstractsAromatic l -amino acid decarboxylase deficiency associated with epilepsy mimicking non-epileptic involuntary movementsDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 11 2008Susumu Ito MD Aromatic l -amino acid decarboxylase (AADC) deficiency is a rare inborn error of neurotransmitter biosynthesis that leads to a combined deficiency of catecholamines and serotonin and is characterized by global developmental delay, involuntary movements, and autonomic dysfunction. We report the case of an 11-year-old male patient with AADC deficiency who also had epileptic spasms and generalized tonic seizures with asymmetrical features, in addition to frequent involuntary non-epileptic movements. The clinical manifestation of the epileptic attacks apparently resembled that of non-epileptic attacks. It was difficult to differentiate between both attacks without the help of an ictal electroencephalographic study. The epileptic attacks were finally controlled by appropriate antiepileptic drugs. Because an association with epileptic seizures is uncommon in AADC deficiency, some cases may have been regarded as involuntary non-epileptic movements. This indicates that the differentiation of epileptic attacks from non-epileptic ones is indispensable for the adequate treatment of patients with AADC deficiency. [source] GABAB receptor expression and function in olfactory receptor neuron axon growthDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2004Catherine A. Priest Abstract Neurotransmitters have been implicated in regulating growth cone motility and guidance in the developing nervous system. Anatomical and electrophysiological studies show the presence of functional GABAB receptors on adult olfactory receptor neuron (ORN) nerve terminals. Using antisera against the GABAB R1a/b receptor isoforms we show that developing mouse olfactory receptor neurons express GABAB receptors from embryonic day 14 through to adulthood. GABAB receptors are present on axon growth cones from both dissociated ORNs and olfactory epithelial explants. Neurons in the olfactory bulb begin to express glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA, from E16 through to adulthood. When dissociated ORNs were cultured in the presence of the GABAB receptor agonists, baclofen or SKF97541, neurite outgrowth was significantly reduced. Concurrent treatment of the neurons with baclofen and the GABAB receptor antagonist CGP54626 prevented the inhibitory effects of baclofen on ORN neurite outgrowth. These results show that growing ORN axons express GABAB receptors and are sensitive to the effects of GABAB receptor activation. Thus, ORNs in vivo may detect GABA release from juxtaglomerular cells as they enter the glomerular layer and use this as a signal to limit their outgrowth and find synaptic targets in regeneration and development. © 2004 Wiley Periodicals, Inc. J Neurobiol 60:154,165, 2004 [source] New prospects for immunotherapy at diagnosis of type 1 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2009Paolo Pozzilli Immune intervention at diagnosis of type 1 diabetes (T1D) aims to prevent or reverse the disease by blocking autoimmunity, thereby preserving/restoring ,-cell mass and function. Recent clinical trials of non-specific and of antigen-specific immune therapies have demonstrated the feasibility of modulation of islet-specific autoimmunity in patients with partial prevention of loss of insulin secretion. In a series of review articles published in this issue of the journal, some of the most promising approaches of immune intervention in T1D are presented. Here we outline the rationale of such interventions and future prospects in this area. Copyright © 2009 John Wiley & Sons, Ltd. Insulin therapy in type 1 diabetes (T1D) rescues the patient from a certain death but not cure the disease. The goal of any therapeutic intervention in T1D is the preservation of insulin-secreting cells; this is achieved by the abrogation of pathogenic reactivity to beta cell autoantigens while preserving full capacity to generate a normal immune response against foreign antigens. Although several therapeutic candidates have been investigated in experimental models of T1D many of which showed promising results, a successful extrapolation of these findings to human T1D has proved to be difficult. In part, this failure results from the considerable disease heterogeneity associated with diverse genetic and non-genetic disease determinants and the spectrum of clinical phenotype at diagnosis. Thus, a younger age at onset is associated with stronger genetic susceptibility, more intense immune response to ,-cell antigens, shorter duration of symptoms, more severe metabolic derangement at diagnosis and a more rapid rate of ,-cell-destruction 1,3. Therefore, designing therapies that would be effective in all clinical settings is definitely challenging. In this issue five different approaches are discussed ranging from antigen-specific therapies [DiaPep277 and glutamic acid decarboxylase(GAD)], to non-antigen-specific immunoregulation (anti-CD3) and to anti-inflammatory (anti-IL1 receptor antagonist). These approaches are currently being tested in large international multicenter trials, and all of them use very similar outcome in terms of a beneficial effect (C-peptide secretion as evidence of a therapeutic effect on restoration of ,-cell function). The authors have been asked to follow a similar format in presenting their approaches so that the reader can easily compare them in terms of rationale and therapeutic goals. [source] Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodiesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2005Bernd Franke Abstract The prodromal phase of type 1 diabetes is characterised by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only ,-cell specific antibodies. There is general consensus that the presence of multiple Aab (, 3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. The most commonly used assay format for the detection of Aab to GAD, IA-2 and insulin is the fluid-phase radiobinding assay. The RBA does not identify or measure Aab, but merely detects its presence. However, on the basis of molecular studies, disease-specific constructs of GAD and IA-2 have been employed leading to somewhat improved sensitivity and specificity of the RBA. Serological studies have shown epitope restriction of IAA that can differentiate diabetes-related from unrelated IAA, but current assays do not distinguish between disease-predictive and non-predictive IAA or between IAA and insulin antibodies (IA). More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA. Copyright © 2005 John Wiley & Sons, Ltd. [source] Genetic and perinatal factors as risk for childhood type 1 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2004Karin Larsson Abstract The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility of identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10 000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase,related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes. Copyright © 2004 John Wiley & Sons, Ltd. [source] The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitusDIABETIC MEDICINE, Issue 2 2008A. W. Van Deutekom Abstract Latent autoimmune diabetes in the adult (LADA) is a slowly progressive form of autoimmune diabetes, characterized by diabetes-associated autoantibody positivity. A recent hypothesis proposes that LADA consists of a heterogeneous population, wherein several subgroups can be identified based on their autoimmune status. A systematic review of the literature was carried out to appraise whether the clinical characteristics of LADA patients correlate with the titre and numbers of diabetes-associated autoantibodies. We found that the simultaneous presence of multiple autoantibodies and/or a high-titre anti-glutamic acid decarboxylase (GAD),compared with single and low-titre autoantibody,is associated with an early age of onset, low fasting C-peptide values as a marker of reduced pancreatic B-cell function, a high predictive value for future insulin requirement, the presence of other autoimmune disorders, a low prevalence of markers of the metabolic syndrome including high body mass index, hypertension and dyslipidaemia, and a high prevalence of the genotype known to increase the risk of Type 1 diabetes. We propose a more continuous classification of diabetes mellitus, based on the finding that the clinical characteristics gradually change from classic Type 1 diabetes to LADA and finally to Type 2 diabetes. Future studies should focus on determining optimal cut-off points of anti-GAD for differentiating clinically relevant diabetes mellitus subgroups. [source] Islet autoimmunity and genetic mutations in Chinese subjects initially thought to have Type 1B diabetesDIABETIC MEDICINE, Issue 1 2006D. Zhang Abstract Aims To explore the contribution of islet autoimmunity and genetic mutations in Chinese patients initially thought to have Type 1B diabetes. Methods A group of 33 Chinese patients with newly diagnosed Type 1B diabetes, were identified by the absence of autoantibodies to glutamic acid decarboxylase (GAD), IA-2, insulin, thyroid globulin or thyroid peroxidase, or high-risk HLA-DQ haplotypes. The cohort was further characterized by measurement of autoantibodies to carboxypeptidase H (CPH) and SOX13 using radioligand assays, and testing for genetic mutations associated with MODY3/MODY6 and mitochondrial diabetes. Mutations of HNF-1, (MODY3) and neuroD1/,2 (MODY6) genes were screened using the single-strand conformation polymorphism (SSCP) technique and sequencing. Mitochondrial DNA mutations were analysed with polymerase chain reaction,restriction fragment length polymorphism (PCR-RFLP). Results Within the cohort, we found one patient with a novel mutation, R321H (CGC,CAC) in exon 5 of the HNF-1, gene, one with ND1 mt3316 G,A mutation in mitochondrial DNA, five with Ala45Thr polymorphisms in the neuroD1/,2 gene, and two patients with autoantibodies to SOX13. Conclusions Some of the Chinese patients originally thought to have Type 1B diabetes do have other evidence of islet autoimmunity and genetic mutations involved in the underlying aetiology. This suggests that more rigorous screening for these conditions is needed before classifying subjects as having Type 1B diabetes. [source] Autoantibodies to the islet cell antigen SOX-13 are associated with duration but not type of diabetesDIABETIC MEDICINE, Issue 3 2003T. M. E. Davis Abstract Aims The autoantigen SOX-13 of the SRY-related high mobility group box is a low-frequency reactant in sera from patients with Type 1 diabetes. We further investigated the potential diagnostic role of anti-SOX-13, and in particular its ability to distinguish Type 1 from Type 2 diabetes, in two large, well-characterized cohorts. Methods SOX-13 autoantibody status was ascertained using a radioimmunoprecipitation assay in (i) a random sample of 546 participants in an Australian community-based study (the Fremantle Diabetes Study; FDS) of whom 119 had Type 1 and 427 Type 2 diabetes, and (ii) a sample of 333 subjects with Type 2 diabetes from the United Kingdom Prospective Diabetes Study (UKPDS) stratified by age, anti-glutamic acid decarboxylase (GAD) and islet cell antibody (ICA) status, and requirement for insulin therapy within 6 years of diagnosis. Results The frequencies of anti-SOX-13 in the FDS subjects were 16.0% and 14.8% for Type 1 and Type 2 patients, respectively, and levels were similar. In the UKPDS subjects, the frequency was 4.5%. In a logistic regression model involving demographic, anthropometric and metabolic variables, only diabetes duration was significantly associated with anti-SOX-13 positivity, especially for duration > 5 years (P < 0.002). When the coexistence of autoantibodies was assessed in the two study samples, there were no significant associations between anti-SOX-13 and ICA, anti-GAD or ICA512/IA-2. Conclusions Whilst the frequency of anti-SOX-13 may be increased in some populations of diabetic patients, this reactivity does not usefully distinguish Type 1 from Type 2 diabetes. However, the association with diabetes duration suggests that anti-SOX-13 may be a non-specific marker of tissue damage associated with chronic hyperglycaemia. Diabet. Med. 20, 198,204 (2003) [source] Heterogeneity of non-insulin-dependent diabetes expressed as variability in insulin sensitivity, ,-cell function and cardiovascular risk profileDIABETIC MEDICINE, Issue 1 2003K. I. Birkeland Abstract Aims The present study investigated the variability in insulin sensitivity and ,-cell function and their relationship to anti-glutamic acid decarboxylase (GAD) positivity and the metabolic syndrome in a group of patients with non-insulin-dependent diabetes mellitus (NIDDM). Methods Fifty-four subjects aged 59.5 ± 6.1 (mean ± sd) years with NIDDM for 7.9 ± 3.9 years referred to hospital due to poor glycaemic control, were investigated. Insulin sensitivity was determined by the euglycaemic hyperinsulinaemic glucose clamp technique as the glucose disposal rate relative to the insulin level obtained (GDRI), and also estimated with the homeostasis model assessment (HOMA-S). ,-cell function was measured by assaying the fasting and glucagon-stimulated C-peptide levels and with the HOMA-B. Results The insulin sensitivity varied 18-fold between subjects when estimated with the clamp and six-fold when estimated with HOMA-S, and was lower the more criteria for the metabolic syndrome present (P = 0.0001 by anova). The ,-cell function varied four-fold when measured as stimulated C-peptide, and eight-fold when estimated with the HOMA-B. The levels of fasting C-peptide and HOMA-B values tended to be lower in anti-GAD+ (n = 11) than in anti-GAD,subjects (P = 0.06 and P = 0.08, respectively). From previously published coronary risk charts, we estimated the 10-year risk of a coronary heart disease (CHD) event to be > 20% in 17 of 39 patients free from cardiovascular disease at the time of study, 16 of whom qualified for a diagnosis of the metabolic syndrome. Conclusions The wide variations in insulin sensitivity and ,-cell function found among subjects with NIDDM support the notion that the disorder is highly heterogeneous. Reduced insulin sensitivity was clearly related to the metabolic syndrome and an increased risk for CHD. [source] PRECLINICAL STUDY: Mice lacking Gad2 show altered behavioral effects of ethanol, flurazepam and gabaxadolADDICTION BIOLOGY, Issue 1 2010Yuri A. Blednov ABSTRACT ,-Aminobutyric acid (GABA) is synthesized in brain by two isoforms of glutamic acid decarboxylase (Gad), Gad1 and Gad2. Gad1 provides most of the GABA in brain, but Gad2 can be rapidly activated in times of high GABA demand. Mice lacking Gad2 are viable whereas deletion of Gad1 is lethal. We produced null mutant mice for Gad2 on three different genetic backgrounds: predominantly C57BL/6J and one or two generations of backcrossing to 129S1/SvimJ (129N1, 129N2). We used these mice to determine if actions of alcohol are regulated by synthesis of GABA from this isoform. We also studied behavioral responses to a benzodiazepine (flurazepam) and a GABAA receptor agonist (gabaxadol). Deletion of Gad2 increased ethanol palatability and intake and slightly reduced the severity of ethanol-induced withdrawal, but these effects depended strongly on genetic background. Mutant mice on the 129N2 background showed the above three ethanol behavioral phenotypes, but the C57BL/6J inbred background did not show any of these phenotypes. Effects on ethanol consumption also depended on the test as the mutation did not alter consumption in limited access models. Deletion of Gad2 reduced the effect of flurazepam on motor incoordination and increased the effect of extrasynaptic GABAA receptor agonist gabaxadol without changing the duration of loss of righting reflex produced by these drugs. These results are consistent with earlier proposals that deletion of Gad2 (on 129N2 background) reduces synaptic GABA but also suggest changes in extrasynaptic receptor function. [source] Learning-associated regulation of polysialylated neural cell adhesion molecule expression in the rat prefrontal cortex is region-, cell type- and paradigm-specificEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2008Judith P. F. Ter Horst Abstract The prefrontal cortex (PFC) is an interconnected set of cortical areas that function in the synthesis of a diverse range of information and production of complex behaviour. It is now clear that these frontal structures, through bidirectional excitatory communication with the hippocampal formation, also play a substantial role in long-term memory consolidation. In the hippocampus, morphological synaptic plasticity, supported by regulation of neural cell adhesion molecule (NCAM) polysialylation status, is crucial to information storage. The recent description of polysialylated neurons in the various fields of the medial PFC suggests these structures to possess a similar capacity for synaptic plasticity. Here, using double-labelling immunohistochemistry with glutamic acid decarboxylase 67, we report that the nature of NCAM polysialic acid-positive neurons in the PFC is region-specific, with a high proportion (30,50%) of a ,-aminobutyric acid (GABA)ergic phenotype in the more ventral infralimbic, orbitofrontal and insular cortices compared with just 10% in the dorsal structures of the cingulate, prelimbic and frontal cortices. Moreover, spatial learning was accompanied by activations in polysialylation expression in ventral PFC structures, while avoidance conditioning involved downregulation of this plasticity marker that was restricted to the dorsomedial PFC , the cingulate and prelimbic cortices. Thus, in contrast to other structures integrated functionally with the hippocampus, memory-associated plasticity mobilized in the PFC is region-, cell type- and task-specific. [source] Depolarization promotes GAD 65-mediated GABA synthesis by a post-translational mechanism in neural stem cell-derived neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2008Nidhi Gakhar-Koppole Abstract Neuronal activity regulates neurogenesis and neuronal differentiation in the mammalian brain. The commencement of neurotransmitter expression establishes the neuronal phenotype and enables the formation of functional connectivity between neurons. In addition, release of neurotransmitters from differentiating neurons may modulate the behaviour of neural precursors. Here, we show that neuronal activity regulates ,-aminobutyric acid (GABA) expression in neurons generated from stem cells of the striatum and adult subventricular zone (SVZ). Differentiating neurons display spontaneous Ca2+ events, which are voltage-gated calcium channel (VGCC) dependent. Depolarization increases both the frequency of Ca2+ transients and the amount of Ca2+ influx in differentiating neurons. We show that depolarization-dependent GABA expression is regulated by the amplitude and not by the frequency of Ca2+ influx. Brief activation of VGCCs leads to Ca2+ influx that in turn promotes a rapid expression of GABA. Depolarization-dependent GABA expression does not require changes in gene expression. Instead, it involves cAMP-dependent protein kinase (PKA) and Ca2+ and phospholipid-dependent protein kinase (PKC) signalling. Activity increases the number of glutamic acid decarboxylase (GAD) 65-immunoreactive neurons in a PKA-dependent manner, without altering the expression of GAD 65, suggesting that depolarization promotes recruitment of GAD 65 by a post-translational mechanism. In line with this, depolarization does not permanently increase the expression of GABA in neurons derived from neural stem cells of the embryonic striatum, cortex and adult SVZ. Thus, neuronal activity does not merely accelerate neuronal differentiation but it may alter the mechanism of GABA synthesis in newly generated neurons. [source] Glutamatergic neurons are present in the rat ventral tegmental areaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2007Tsuyoshi Yamaguchi Abstract The ventral tegmental area (VTA) is thought to play an important role in reward function. Two populations of neurons, containing either dopamine (DA) or ,-amino butyric acid (GABA), have been extensively characterized in this area. However, recent electrophysiological studies are consistent with the notion that neurons that utilize neurotransmitters other than DA or GABA are likely to be present in the VTA. Given the pronounced phenotypic diversity of neurons in this region, we have proposed that additional cell types, such as those that express the neurotransmitter glutamate may also be present in this area. Thus, by using in situ hybridization histochemistry we investigated whether transcripts encoded by genes for the two vesicular glutamate transporters, VGluT1 or VGluT2, were expressed in the VTA. We found that VGluT2 mRNA but not VGluT1 mRNA is expressed in the VTA. Neurons expressing VGluT2 mRNA were differentially distributed throughout the rostro-caudal and medio-lateral aspects of the VTA, with the highest concentration detected in rostro-medial areas. Phenotypic characterization with double in situ hybridization of these neurons indicated that they rarely co,expressed mRNAs for tyrosine hydroxylase (TH, marker for DAergic neurons) or glutamic acid decarboxylase (GAD, marker for GABAergic neurons). Based on the results described here, we concluded that the VTA contains glutamatergic neurons that in their vast majority are clearly non-DAergic and non-GABAergic. [source] Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2003Simone M. Smits Abstract The mesencephalic dopaminergic (mesDA) system is involved in many brain functions including motor control and motivated behaviour, and is of clinical importance because of its implication in psychiatric disorders and Parkinson's disease. Nurr1, a member of the nuclear hormone receptor superfamily of transcription factors, is essential for establishing the dopaminergic phenotype, because expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, requires Nurr1. In addition, Nurr1 plays an important role in the maintenance of mesDA neurons. Neonatal Nurr1 knockout mice lack expression of the dopamine transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and l -aromatic amino acid decarboxylase (AADC) in addition to TH specifically in mesDA neurons. It is unclear whether the lack of expression of these dopaminergic markers is caused by a maintenance defect or whether the induction of these markers depends on Nurr1 expression. To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14.5. Here we demonstrate that induction of VMAT2 and DAT specifically in mesDA neurons requires Nurr1 expression, whereas AADC expression in mesDA neurons is induced independently of Nurr1 function. [source] Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2002Sangmi Chung Abstract Nurr1 is a transcription factor critical for the development of midbrain dopaminergic (DA) neurons. This study modified mouse embryonic stem (ES) cells to constitutively express Nurr1 under the elongation factor-1, promoter. The Nurr1-expression in ES cells lead to up-regulation of all DA neuronal markers tested, resulting in about a 4- to 5-fold increase in the proportion of DA neurons. In contrast, other neuronal and glial markers were not significantly changed by Nurr1 expression. It was also observed that there was an additional 4-fold increase in the number of DA neurons in Nurr1-expressing clones following treatment with Shh, FGF8 and ascorbic acid. Several lines of evidence suggest that these neurons may represent midbrain DA neuronal phenotypes; firstly, they coexpress midbrain DA markers such as aromatic l -amino acid decarboxylase, calretinin, and dopamine transporter, in addition to tyrosine hydroxylase and secondly, they do not coexpress other neurotransmitters such as GABA or serotonin. Finally, consistent with an increased number of DA neurons, the Nurr1 transduction enhanced the ability of these neurons to produce and release DA in response to membrane depolarization. This study demonstrates an efficient genetic manipulation of ES cells that facilitates differentiation to midbrain DA neurons, and it will serve as a framework of genetic engineering of ES cells by key transcription factor to regulate their cell fate. [source] Circadian rhythm of aromatic l -amino acid decarboxylase in the rat suprachiasmatic nucleus: gene expression and decarboxylating activity in clock oscillating cellsGENES TO CELLS, Issue 5 2002Yoshiki Ishida Background: Aromatic l -amino acid decarboxylase (AADC) is the enzyme responsible for the decarboxylation step in both the catecholamine and indoleamine synthetic pathways. In the brain, however, a group of AADC containing neurones is found outside the classical monoaminergic cell groups. Since such non-monoaminergic AADC is expressed abundantly in the suprachiasmatic nucleus (SCN), the mammalian circadian centre, we characterized the role of AADC in circadian oscillation. Results : AADC gene expression was observed in neurones of the dorsomedial subdivision of the SCN and its dorsal continuant in the anterior hypothalamic area. These AADC neurones could uptake exogenously applied L-DOPA and formed dopamine. AADC was co-expressed with vasopressin and the clock gene Per1 in the neurones of the SCN. Circadian gene expression of AADC was observed with a peak at subjective day and a trough at subjective night. The circadian rhythm of AADC enzyme activity in the SCN reflects the expression of the gene. Conclusions: Non-monoaminergic AADC in the SCN is expressed in clock oscillating cells, and the decarboxylating activity of master clock cells are under the control of the circadian rhythm. [source] Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant miceGENES, BRAIN AND BEHAVIOR, Issue 2 2003O. Stork We investigated the involvement of the 65 kDa isoform of glutamic acid decarboxylase (GAD65) and GAD65-mediated ,-aminobutyric acid (GABA) synthesis in the formation and expression of Pavlovian fear memory. To this end, behavioral, endocrine and autonomic parameters were examined during conditioned fear retrieval of mice with targeted ablation of the GAD65 gene (GAD65,/, mice). These mutant mice were found to display specific fear behavior (freezing, escape), as well as autonomic (increased defecation) and endocrine activation (increased plasma corticosterone) during fear memory retrieval. However, freezing was reduced and flight and escape behavior were increased in GAD65,/, mice compared to their wild type and heterozygous littermates, while corticosterone levels and defecation rates did not differ between genotypes. Active defensive behavior of GAD65,/, mice was observed during both auditory cued and contextual retrieval of fear memory, as well as immediately after conditioning. These data indicate a selectively altered behavioral fear response in GAD65,/, mice, most likely due to deficits in threat estimation or the elicitation of appropriate conditioned fear behavior, and suggest that GAD65 is a genetic determinant of conditioned fear behavior. GAD65,/, mice provide a valuable tool to further dissect the GABAergic mechanisms involved in fear and anxiety and to model GABA-related neurological and psychiatric disorders. [source] Combining fMRI and SNP data to investigate connections between brain function and genetics using parallel ICA,HUMAN BRAIN MAPPING, Issue 1 2009Jingyu Liu Abstract There is current interest in understanding genetic influences on both healthy and disordered brain function. We assessed brain function with functional magnetic resonance imaging (fMRI) data collected during an auditory oddball task,detecting an infrequent sound within a series of frequent sounds. Then, task-related imaging findings were utilized as potential intermediate phenotypes (endophenotypes) to investigate genomic factors derived from a single nucleotide polymorphism (SNP) array. Our target is the linkage of these genomic factors to normal/abnormal brain functionality. We explored parallel independent component analysis (paraICA) as a new method for analyzing multimodal data. The method was aimed to identify simultaneously independent components of each modality and the relationships between them. When 43 healthy controls and 20 schizophrenia patients, all Caucasian, were studied, we found a correlation of 0.38 between one fMRI component and one SNP component. This fMRI component consisted mainly of parietal lobe activations. The relevant SNP component was contributed to significantly by 10 SNPs located in genes, including those coding for the nicotinic ,-7cholinergic receptor, aromatic amino acid decarboxylase, disrupted in schizophrenia 1, among others. Both fMRI and SNP components showed significant differences in loading parameters between the schizophrenia and control groups (P = 0.0006 for the fMRI component; P = 0.001 for the SNP component). In summary, we constructed a framework to identify interactions between brain functional and genetic information; our findings provide a proof-of-concept that genomic SNP factors can be investigated by using endophenotypic imaging findings in a multivariate format. Hum Brain Mapp, 2009. © 2007 Wiley-Liss, Inc. [source] Mutations in human monoamine-related neurotransmitter pathway genes,HUMAN MUTATION, Issue 7 2008Jan Haavik Abstract Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (D,H), and phenylethanolamine N -methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O -methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org). Hum Mutat 29(7), 891,902, 2008. © 2008 Wiley-Liss, Inc. [source] Secondary neurogenesis and telencephalic organization in zebrafish and mice: a brief reviewINTEGRATIVE ZOOLOGY (ELECTRONIC), Issue 1 2009Mario F. WULLIMANN Abstract Most zebrafish neurodevelopmental studies have focused on the embryo, which is characterized by primary neurogenesis of mostly transient neurons. Secondary neurogenesis becomes dominant in the hatching larva, when major brain parts are established and begin to differentiate. This developmental period allows for a comparative analysis of zebrafish brain organization with amniotes at equivalent stages of neurogenesis. Within a particular time window, the early forebrains of mice (Embyronic stage [E] 12.5/13.5 days [d]) and zebrafish (3 d) reveal highly comparable expression patterns of genes involved in neurogenesis, for example proneural and other transcription factors (Neurogenin1, NeuroD, Mash1/Zashla and Pax6). Further topological correspondences are seen in the expression of LIM and homeobox genes, such as Lhx6/7, Tbr2 and Dlx2a. When this analysis is extended to gamma-aminobutyric acid/glutamic acid decarboxylase (GABA/GAD) cell patterns during this critical time window, an astonishing degree of similarity between the two species is again seen, for example regarding the presence of GABA/GAD cells in the subpallium, with the pallium only starting to be invaded by such cells from the subpallium. Furthermore, the expression of proneural and other genes correlates with GABA cell patterns (e.g. Mash1/Zash1a gene expression in GABA-positive and Neurogenin1/NeuroD in GABA-negative telencephalic regions) in mice and zebrafish. Data from additional vertebrates, such as Xenopus, are also highly consistent with this analysis. Therefore, the vertebrate forebrain appears to undergo a phylotypic stage of secondary neurogenesis, characterized by regionally separated GABAergic (inhibitory) versus glutamatergic (excitatory) cell production sites, which are obscured later in development by tangential migration. This period is highly advantageous for molecular neuroanatomical cross-species comparisons. [source] GABA synthesis in Schwann cells is induced by the neuroactive steroid allopregnanoloneJOURNAL OF NEUROCHEMISTRY, Issue 4 2010Valerio Magnaghi J. Neurochem. (2009) 112, 980,990. Abstract Recent evidence showed that neurotransmitters are synthesised in glial cells, such as the Schwann cells, which form myelin sheaths in the PNS. While the presence of GABA type A (GABA-A) receptors has been previously demonstrated in these cells, the evidence of GABA synthesis remained still elusive. In an attempt to demonstrate the presence of GABA in rat Schwann cells, we adopted a strategy, using several integrated neurochemical, molecular as well as immunocytochemical approaches. We first demonstrated the presence of glutamic acid decarboxylase of 67 kDa (GAD67) in Schwann cells, a crucial enzyme of the GABA synthesis mechanism. Second, we demonstrated that GABA is synthesized and localized in Schwann cells. As the third step we showed that allopregnanolone (10 nM), a potent allosteric modulator of GABA-A receptors, stimulates GABA synthesis through increased levels of GAD67 in Schwann cells. Analysis of intracellular signalling mechanisms revealed that the protein kinase A pathway, through enhanced cAMP levels and cAMP response element binding protein phosphorylation, modulates the allosteric action of allopregnanolone at the GABA-A receptor in Schwann cells. Our findings are the first to demonstrate that this GABA mechanism is active in Schwann cells thus establishing new potential therapeutic targets to control Schwann cell biology, which may prove useful in the treatment of several neurodegenerative disorders. [source] Endogenously released DOPA is a causal factor for glutamate release and resultant delayed neuronal cell death by transient ischemia in rat striataJOURNAL OF NEUROCHEMISTRY, Issue 3 2001Nobuya Furukawa Glutamate is implicated in neuronal cell death. Exogenously applied DOPA by itself releases neuronal glutamate and causes neuronal cell death in in vitro striatal systems. Herein, we attempt to clarify whether endogenous DOPA is released by 10 min transient ischemia due to four-vessel occlusion during rat striatal microdialysis and, further, whether DOPA, when released, functions to cause glutamate release and resultant delayed neuronal cell death. Ischemia increased extracellular DOPA, dopamine, and glutamate, and elicited neuronal cell death 96 h after ischemic insult. Inhibition of striatal l -aromatic amino acid decarboxylase 10 min before ischemia increased markedly basal DOPA, tripled glutamate release with a tendency of decrease in dopamine release by ischemia, and exaggerated neuronal cell death. Intrastriatal perfusion of 10,30 nm DOPA cyclohexyl ester, a competitive DOPA antagonist, 10 min before ischemia, concentration-dependently decreased glutamate release without modification of dopamine release by ischemia. At 100 nm, the antagonist elicited a slight ceiling effect on decreases in glutamate release by ischemia and protected neurons from cell death. Glutamate was released concentration-dependently by intrastriatal perfusion of 0.3,1 mm DOPA and stereoselectively by 0.6 mm DOPA. The antagonist elicited no hypothermia during and after ischemia. Endogenously released DOPA is an upstream causal factor for glutamate release and resultant delayed neuronal cell death by brain ischemia in rat striata. DOPA antagonist has a neuroprotective action. [source] Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4/5 Prevent the Death of Striatal Projection Neurons in a Rodent Model of Huntington's DiseaseJOURNAL OF NEUROCHEMISTRY, Issue 5 2000Esther Pérez-Navarro Abstract: Intrastriatal injection of quinolinate has been proven to be a very useful animal model to study the pathogenesis and treatment of Huntington's disease. To determine whether growth factors of the neurotrophin family are able to prevent the degeneration of striatal projection neurons, cell lines expressing brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5 (NT-4/5) were grafted in the adult rat striatum before quinolinate injection. Three days after lesioning, ongoing cell death was assessed by in situ detection of DNA fragmentation. In animals grafted with the control cell line, quinolinate injection induced a gradual cell loss that was differentially prevented by intrastriatal grafting of BDNF-, NT-3-, or NT-4/5-secreting cells. Seven days after lesioning, we characterized striatal projection neurons that were protected by neurotrophins. Quinolinate injection, alone or in combination with the control cell line, induced a selective loss of striatal projection neurons. Grafting of a BDNF-secreting cell line prevented the loss of all types of striatal projection neurons analyzed. Glutamic acid decarboxylase 67-, preproenkephalin-, and preprotachykinin A- but not prodynorphin-expressing neurons were protected by grafting of NT-3- or NT-4/5-secreting cells but with less efficiency than the BDNF-secreting cells. Our findings show that neurotrophins are able to promote the survival of striatal projection neurons in vivo and suggest that BDNF might be beneficial for the treatment of striatonigral degenerative disorders, including Huntington's disease. [source] Expression of GABAB Receptors in Magnocellular Neurosecretory Cells of Male, Virgin Female and Lactating RatsJOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2005D. S. Richards Abstract GABA is one of the key neurotransmitters that regulate the firing activity of neurones in the supraoptic (SON) and paraventricular (PVN) nuclei. In the present study, we used immunohistochemical techniques to study the distribution and subcellular localisation of metabotropic GABAB receptors in magnocellular neurones in the SON and PVN. Robust GABAB receptor immunoreactivity (GABABR; both subunit 1 and subunit 2 of the heterodimer), was observed in the SON and PVN. At the light microcope level, GABABR immonoreactivity displayed a clustered pattern localised both intracytoplasmically and at the plasma membrane. Densitometry analysis indicated that GABABR immunoreactivity was significantly more intense in vasopressin cells than in oxytocin cells, both in male, virgin female and lactating rats, and was denser in males than in virgin females. Light and electron microscope studies indicated that cytoplasmic GABABR was localised in various organelles, including the Golgi, early endosomes and lysosomes, suggesting the cycling of the receptor within the endocytic and trafficking pathways. Some smaller clusters at the level of the cell plasma membrane were apposed to glutamic acid decarboxylase 67 immunoreactive boutons, and appeared to be colocalised with gephyrin, a constituent protein of the postsynaptic density at inhibitory synapses. The presence of GABABR immunoreactivity at synaptic and extrasynaptic sites was supported by electron microscopy. These results provide anatomical evidence for the expression of postsynaptic GABAB receptors in magnocellular neurosecretory cells. [source] Chemical Coding of GABAB Receptor-Immunoreactive Neurones in Hypothalamic Regions Regulating Body WeightJOURNAL OF NEUROENDOCRINOLOGY, Issue 1 2003M. Bäckberg Abstract ,-aminobutyric acid (GABA) interacts with hypothalamic neuronal pathways regulating feeding behaviour. GABA has been reported to stimulate feeding via both ionotropic GABAA and metabotropic GABAB receptors. The functional form of the GABAB receptor is a heterodimer consisting of GABAB receptor-1 (GABABR1) and GABAB receptor-2 (GABABR2) proteins. Within the heterodimer, the GABA-binding site is localized to GABABR1. In the present study, we used an antiserum to the GABABR1 protein in order to investigate the cellular localization of GABABR1-immunoreactive neurones in discrete hypothalamic regions implicated in the control of body weight. The colocalization of GABABR1 immunoreactivity with different chemical messengers that regulate food intake was analysed. GABABR1-immunoreactive cell bodies were found in the periventricular, paraventricular (PVN), supraoptic, arcuate, ventromedial hypothalamic, dorsomedial hypothalamic, tuberomammillary nuclei and lateral hypothalamic area (LHA). Direct double-labelling showed that glutamic acid decarboxylase (GAD)-positive terminals were in close contact with GABABR1-containing cell bodies located in all these regions. In the ventromedial part of the arcuate nucleus, GABABR1-immunoreactive cell bodies were found to contain neuropeptide Y, agouti-related peptide (AGRP) and GAD. In the ventrolateral part of the arcuate nucleus, GABABR1-immunoreactive cell bodies were shown to contain pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript. In the LHA, GABABR1 immunoreactivity was present in both melanin-concentrating hormone- and orexin-containing cell populations. In the tuberomammillary nucleus, GABABR1-immunoreactive cell bodies expressed histidine decarboxylase, a marker for histamine-containing neurones. In addition, GAD and AGRP were found to be colocalized in some nerve terminals surrounding GABABR1-immunoreactive cell bodies in the parvocellular part of the PVN. The results may provide a morphological basis for the understanding of how GABA regulates the hypothalamic control of food intake and body weight via GABAB receptors. [source] Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase allelesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2003Susanna Althini Abstract We investigated the use of the mouse tyrosine hydroxylase (TH) gene to drive knock-in constructs in catecholaminergic neurons. Two targeting constructs representing truncated forms of either of the BMP receptors ALK-2 or BMPR-II preceded by an internal ribosome entry site (IRES) were introduced into the 3, untranslated region of TH. An frt-flanked neomycin-resistance (neor) cassette was placed in the 3, end of the targeting constructs. Mice homozygous for the knock-in alleles showed various degrees of hypokinetic behavior, depending mainly on whether the neor cassette was removed. In situ hybridization and immunohistochemistry showed that TH mRNA and protein were variously down-regulated in these mouse strains. Reduced levels of dopamine and noradrenalin were found in several brain areas. However, number and morphology of neurons in substantia nigra and their projections to striatum appeared normal in the neor -positive TH hypomorphic mice as examined by markers for L-aromatic amino acid decarboxylase and the dopamine transporter. Elimination of the neor cassette from the knock-in alleles partially restored TH and dopamine levels. The present neor -positive TH hypomorphic mice show that nigrostriatal innervation develops independently of TH and should find use as a model for conditions of reduced catecholamine synthesis, as seen in, for example, L-dihydroxyphenylalanine-responsive dystonia/infantile parkinsonism. © 2003 Wiley-Liss, Inc. [source] Melatonin induces tyrosine hydroxylase mRNA expression in the ventral mesencephalon but not in the hypothalamusJOURNAL OF PINEAL RESEARCH, Issue 1 2002José L Venero We have evaluated the effect of chronic administration of melatonin in terms of mRNA expression for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, and in the terms of dopamine (DA) transporter (DAT) by means of in situ hybridization. Experimental rats received daily late afternoon injections of 1.5 mg/kg melatonin for 30 days and analysis were performed in the ventral mesencephalon including the substantia nigra (SN) and ventral tegmental area (VTA), and hypothalamus. In the ventral mesencephalon, melatonin treatment significantly induced TH mRNA levels in individual dopaminergic neurons in SN and VTA. In contrast, DAT mRNA levels remained at control levels. Striatal synaptosomal DA uptake was not modified by melatonin treatment as compared with controls. Analysis of glutamic acid decarboxylase (GAD) mRNA in SN, the biosynthetic enzyme for GABAergic neurons, revealed no effect of melatonin treatment on mRNA levels for this marker. In the hypothalamus, we performed mRNA quantitation for TH in arcuate nucleus (Arc) and supraoptic nucleus (SO). Melatonin treatment failed to alter mRNA levels in either area. We detected weak but significant mRNA levels for DAT in Arc, SO, zona incerta (ZI) and periventricular hypothalamic nucleus (Pe). However, because of the low levels of mRNA in hypothalamic areas we were unable to perform a reliable measurement of DAT mRNA levels in response to melatonin treatment. We conclude that melatonin administration, that combines antioxidant capacity and a tissue-specific TH inducing effect, may be useful as a pharmacological agent to protect dopaminergic neurons from degeneration. [source] Differential Adaptations in GABAergic and Glutamatergic Systems During Ethanol Withdrawal in Male and Female RatsALCOHOLISM, Issue 6 2005P E. Alele Background: There are significant and consistent sex differences in recovery from ethanol withdrawal in our animal model of ethanol dependence. We have also observed significant and varied sex differences in subunit protein levels of ,-aminobutyric acid A (GABAA) and the N-metheyl-D-aspartate subtype of glutamate receptors occurring with ethanol dependence and withdrawal. Considering the major role of these two systems as targets of ethanol, we wanted to explore additional possible mechanisms underlying changes in GABAergic and glutamatergic responses after chronic ethanol exposure. Therefore, the objective of the present study was to examine GABAergic- and glutamatergic-associated proteins at three days of ethanol withdrawal, when female rats appear to have largely recovered but male rats still display robust signs of withdrawal. Methods: Male and female rats were fed 6% ethanol in a nutritionally complete liquid diet for 14 days according to a pair-fed design; withdrawal was initiated by replacement of the diet with chow. At three days of withdrawal, the cerebral cortex and hippocampus were dissected for use in Western blot analysis. The paired design was maintained throughout all experimental procedures. Results: At three days of ethanol withdrawal, we found region-specific and sex-selective alterations in levels of GAD (glutamic acid decarboxylase, GABA synthetic enzyme), GABA and glutamate transporters, and the synapse-associated proteins HSP70, PSD-95, and synaptophysin. There were also several significant differences in transporter function at this time that varied between males and females. Conclusions: Taken together, these findings show differential adaptations of GABAergic and glutamatergic neurotransmission between female and male rats that are associated with withdrawal recovery. This suggests that selective withdrawal-induced neuroadaptations in regulation of these systems' activities underlie, at least in part, sex differences in withdrawal recovery between male and female rats. [source] Stiff man syndrome and related conditionsMOVEMENT DISORDERS, Issue 5 2002Hans-Michael Meinck MD Abstract The stiff man syndrome (SMS) and its variants, focal SMS, stiff limb (or leg) syndrome (SLS), jerking SMS, and progressive encephalomyelitis with rigidity and myoclonus (PERM), appear to occur more frequently than hitherto thought. A characteristic ensemble of symptoms and signs allows a tentative clinical diagnosis. Supportive ancillary findings include (1) the demonstration of continuous muscle activity in trunk and proximal limb muscles despite attempted relaxation, (2) enhanced exteroceptive reflexes, and (3) antibodies to glutamic acid decarboxylase (GAD) in both serum and spinal fluid. Antibodies to GAD are not diagnostic or specific for SMS and the role of these autoantibodies in the pathogenesis of SMS/SLS/PERM is the subject of debate and difficult to reconcile on the basis of our present knowledge. Nevertheless, evidence is emerging to suggest that SMS/SLS/PERM are manifestations of an immune-mediated chronic encephalomyelitis and immunomodulation is an effective therapeutic approach. © 2002 Movement Disorder Society [source] Distinct patterns of serum immunoreactivity as evidence for multiple brain-directed autoantibodies in juvenile neuronal ceroid lipofuscinosisNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2006M. J. Lim Autoantibodies to glutamic acid decarboxylase (GAD65) have been reported in sera from the Cln3,/, mouse model of juvenile neuronal ceroid lipofuscinosis (JNCL), and in individuals with this fatal paediatric neurodegenerative disorder. To investigate the existence of other circulating autoreactive antibodies, we used sera from patients with JNCL and other forms of neuronal ceroid lipofuscinosis (NCL) as primary antisera to stain rat and human central nervous system sections. JNCL sera displayed characteristic patterns of IgG, but not IgA, IgE or IgM immunoreactivity that was distinct from the other forms of NCL. Immunoreactivity of JNCL sera was not confined to GAD65-positive (GABAergic) neurons, but also stained multiple other cell populations. Preadsorption of JNCL sera with recombinant GAD65 reduced the intensity of the immunoreactivity, but did not significantly change its staining pattern. Moreover, sera from Stiff Person Syndrome and Type I Diabetes, disorders in which GAD65 autoantibodies are present, stained with profiles that were markedly different from JNCL sera. Collectively, these studies provide evidence of the presence of autoreactive antibodies within multiple forms of NCL, and are not exclusively directed towards GAD65. [source] | ||||||||||||||||