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Michael Aschner - One of the best experts on this subject based on the ideXlab platform.
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valproate and sodium butyrate attenuate manganese decreased locomotor activity and astrocytic Glutamate Transporters expression in mice
Neurotoxicology, 2017Co-Authors: James Johnson, Michael Aschner, Deok Soo Son, Edward Alain B Pajarillo, Equar Taka, Romonia R Reams, Eun Sook LeeAbstract:Manganese (Mn) is an essential trace element, but chronic overexposure to this metal, either environmentally or occupationally may cause manganism, a disease analogous to Parkinson's disease. Inhibitors of histone deacetylases, such as valproic acid (VPA) and sodium butyrate (NaB) exert neuroprotective effects in various animal models of neurological disorders. Thus, the present study investigated whether VPA or NaB prevent Mn-induced neurotoxicity by assessing locomotor activities and expression of astrocytic Glutamate Transporters, Glutamate Transporter 1 (GLT-1) and Glutamate Aspartate Transporter (GLAST), in C57BL/6 mice. C57BL/6 mice were pretreated with VPA (200mg/kg, i.p.) or NaB (1200mg/kg, i.p.) prior to intranasal instillation of Mn (30mg/kg) continually for 21days, followed by open-field and rota-rod behavioral tests and analyses of astrocytic Glutamate Transporters GLT-1 and GLAST protein/mRNA levels. The results showed that Mn significantly decreased locomotor activity as determined by total distance travelled, stereotypic and ambulatory counts. Mn also significantly decreased rota-rod activity reflecting altered motor coordination. Pretreatment with VPA and NaB with Mn reversed the effects of Mn on the locomotor activity and motor coordination. VPA and NaB also attenuated the Mn-induced decrease in GLT-1 and GLAST mRNA and protein levels in the cerebral cortical and cerebellar regions of mice. These results suggest that VPA and NaB exert protective effects against Mn toxicity seem in vitro are also shown in vivo. VPA and NaB pretreatment in mice enhancing astrocytic Glutamate Transporter GLT-1 expression as well as locomotor activities. Future research endeavors are warranted to determine if the therapeutic potential of VPA and NaB is via common molecular mechanism, namely, inhibition of histone deacetylases.
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transcriptional regulation of the astrocytic excitatory amino acid Transporter 1 eaat1 via nf κb and yin yang 1 yy1
Journal of Biological Chemistry, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, Clifford Kim, Deok Soo Son, Eun Sook LeeAbstract:Astrocytic Glutamate Transporter excitatory amino acid Transporter (EAAT) 1, also known as Glutamate Aspartate Transporter (GLAST) in rodents, is one of two glial Glutamate Transporters that are responsible for removing excess Glutamate from synaptic clefts to prevent excitotoxic neuronal death. Despite its important role in neurophysiological functions, the molecular mechanisms of EAAT1 regulation at the transcriptional level remain to be established. Here, we report that NF-κB is a main positive transcription factor for EAAT1, supported by the following: 1) EAAT1 contains two consensus sites for NF-κB, 2) mutation of NF-κB binding sites decreased EAAT1 promoter activity, and 3) activation of NF-κB increased, whereas inhibition of NF-κB decreased EAAT1 promoter activity and mRNA/protein levels. EGF increased EAAT1 mRNA/protein levels and Glutamate uptake via NF-κB. The transcription factor yin yang 1 (YY1) plays a role as a critical negative regulator of EAAT1, supported by the following: 1) the EAAT1 promoter contains multiple consensus sites for YY1, 2) overexpression of YY1 decreased EAAT1 promoter activity and mRNA/protein levels, and 3) knockdown of YY1 increased EAAT1 promoter activity and mRNA/protein levels. Manganese decreased EAAT1 expression via YY1. Epigenetic modifiers histone deacetylases (HDACs) served as co-repressors of YY1 to further decrease EAAT1 promoter activity, whereas inhibition of HDACs reversed manganese-induced decrease of EAAT1 expression. Taken together, our findings suggest that NF-κB is a critical positive regulator of EAAT1, mediating the stimulatory effects of EGF, whereas YY1 is a negative regulator of EAAT1 with HDACs as co-repressors, mediating the inhibitory effects of manganese on EAAT1 regulation.
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role of transcription factor yin yang 1 in manganese induced reduction of astrocytic Glutamate Transporters putative mechanism for manganese induced neurotoxicity
Neurochemistry International, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, James Johnson, Eun Sook LeeAbstract:Astrocytes are the most abundant non-neuronal glial cells in the brain. Once relegated to a mere supportive role for neurons, contemporary dogmas ascribe multiple active roles for these cells in central nervous system (CNS) function, including maintenance of optimal Glutamate levels in synapses. Regulation of Glutamate levels in the synaptic cleft is crucial for preventing excitotoxic neuronal injury. Glutamate levels are regulated predominantly by two astrocytic Glutamate Transporters, Glutamate Transporter 1 (GLT-1) and Glutamate Aspartate Transporter (GLAST). Indeed, the dysregulation of these Transporters has been linked to several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), as well as manganism, which is caused by overexposure to the trace metal, manganese (Mn). Although Mn is an essential trace element, its excessive accumulation in the brain as a result of chronic occupational or environmental exposures induces a neurological disorder referred to as manganism, which shares common pathological features with Parkinsonism. Mn decreases the expression and function of both GLAST and GLT-1. Astrocytes are commonly targeted by Mn, and thus reduction in astrocytic Glutamate Transporter function represents a critical mechanism of Mn-induced neurotoxicity. In this review, we will discuss the role of astrocytic Glutamate Transporters in neurodegenerative diseases and Mn-induced neurotoxicity.
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genetic dys regulation of astrocytic Glutamate Transporter eaat2 and its implications in neurological disorders and manganese toxicity
Neurochemical Research, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, James Johnson, Eun Sook LeeAbstract:Astrocytic Glutamate Transporters, the excitatory amino acid Transporter (EAAT) 2 and EAAT1 (Glutamate Transporter 1 and Glutamate Aspartate Transporter in rodents, respectively), are the main Transporters for maintaining optimal Glutamate levels in the synaptic clefts by taking up more than 90% of Glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these Transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these Transporters by various modes, such as single nucleotide polymorphisms and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via nuclear factor κB and cAMP response element binding protein at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics and translational regulation of EAAT2.
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manganese causes differential regulation of Glutamate Transporter glast taurine Transporter and metallothionein in cultured rat astrocytes
Neurotoxicology, 2002Co-Authors: Keith M. Erikson, Michael AschnerAbstract:Neurotoxicity due to excessive brain manganese (Mn) can occur due to environmental (air pollution, soil, water) and/ or metabolic aberrations (decreased biliary excretion). Manganese is associated with oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional [Mn], it is likely that in pathological conditions it can reach 100-500 microM. Amino acid (e.g. Aspartate, Glutamate, taurine), as well as divalent metal (e.g. zinc, manganese) concentrations are regulated by astrocytes in the brain. Recently, it has been reported that cultured rat primary astrocytes exposed to Mn displayed decreased Glutamate uptake, thereby, increasing the excitotoxic potential of Glutamate. Since the neurotoxic mechanism(s) Mn employs in terms of Glutamate metabolism is unknown, a primary goal of this study was to link altered Glutamate uptake in Mn exposed astrocytes to alterations in Glutamate Transporter message. Further, we wanted to examine the gene expression of metallothionein (MT) and taurine Transporter (tau-T) as markers of Mn exposure. Glutamate uptake was decreased by nearly 40% in accordance with a 48% decrease in Glutamate/Aspartate Transporter (GLAST) mRNA. Taurine uptake was unaffected by Mn exposure even though tau-T mRNA increased by 123%. MT mRNA decreased in these Mn exposed astrocytes possibly due to altered metal metabolism, although this was not examined. These data show that Glutamate and taurine transport in Mn exposed astrocytes are temporally different.
Eun Sook Lee - One of the best experts on this subject based on the ideXlab platform.
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valproate and sodium butyrate attenuate manganese decreased locomotor activity and astrocytic Glutamate Transporters expression in mice
Neurotoxicology, 2017Co-Authors: James Johnson, Michael Aschner, Deok Soo Son, Edward Alain B Pajarillo, Equar Taka, Romonia R Reams, Eun Sook LeeAbstract:Manganese (Mn) is an essential trace element, but chronic overexposure to this metal, either environmentally or occupationally may cause manganism, a disease analogous to Parkinson's disease. Inhibitors of histone deacetylases, such as valproic acid (VPA) and sodium butyrate (NaB) exert neuroprotective effects in various animal models of neurological disorders. Thus, the present study investigated whether VPA or NaB prevent Mn-induced neurotoxicity by assessing locomotor activities and expression of astrocytic Glutamate Transporters, Glutamate Transporter 1 (GLT-1) and Glutamate Aspartate Transporter (GLAST), in C57BL/6 mice. C57BL/6 mice were pretreated with VPA (200mg/kg, i.p.) or NaB (1200mg/kg, i.p.) prior to intranasal instillation of Mn (30mg/kg) continually for 21days, followed by open-field and rota-rod behavioral tests and analyses of astrocytic Glutamate Transporters GLT-1 and GLAST protein/mRNA levels. The results showed that Mn significantly decreased locomotor activity as determined by total distance travelled, stereotypic and ambulatory counts. Mn also significantly decreased rota-rod activity reflecting altered motor coordination. Pretreatment with VPA and NaB with Mn reversed the effects of Mn on the locomotor activity and motor coordination. VPA and NaB also attenuated the Mn-induced decrease in GLT-1 and GLAST mRNA and protein levels in the cerebral cortical and cerebellar regions of mice. These results suggest that VPA and NaB exert protective effects against Mn toxicity seem in vitro are also shown in vivo. VPA and NaB pretreatment in mice enhancing astrocytic Glutamate Transporter GLT-1 expression as well as locomotor activities. Future research endeavors are warranted to determine if the therapeutic potential of VPA and NaB is via common molecular mechanism, namely, inhibition of histone deacetylases.
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transcriptional regulation of the astrocytic excitatory amino acid Transporter 1 eaat1 via nf κb and yin yang 1 yy1
Journal of Biological Chemistry, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, Clifford Kim, Deok Soo Son, Eun Sook LeeAbstract:Astrocytic Glutamate Transporter excitatory amino acid Transporter (EAAT) 1, also known as Glutamate Aspartate Transporter (GLAST) in rodents, is one of two glial Glutamate Transporters that are responsible for removing excess Glutamate from synaptic clefts to prevent excitotoxic neuronal death. Despite its important role in neurophysiological functions, the molecular mechanisms of EAAT1 regulation at the transcriptional level remain to be established. Here, we report that NF-κB is a main positive transcription factor for EAAT1, supported by the following: 1) EAAT1 contains two consensus sites for NF-κB, 2) mutation of NF-κB binding sites decreased EAAT1 promoter activity, and 3) activation of NF-κB increased, whereas inhibition of NF-κB decreased EAAT1 promoter activity and mRNA/protein levels. EGF increased EAAT1 mRNA/protein levels and Glutamate uptake via NF-κB. The transcription factor yin yang 1 (YY1) plays a role as a critical negative regulator of EAAT1, supported by the following: 1) the EAAT1 promoter contains multiple consensus sites for YY1, 2) overexpression of YY1 decreased EAAT1 promoter activity and mRNA/protein levels, and 3) knockdown of YY1 increased EAAT1 promoter activity and mRNA/protein levels. Manganese decreased EAAT1 expression via YY1. Epigenetic modifiers histone deacetylases (HDACs) served as co-repressors of YY1 to further decrease EAAT1 promoter activity, whereas inhibition of HDACs reversed manganese-induced decrease of EAAT1 expression. Taken together, our findings suggest that NF-κB is a critical positive regulator of EAAT1, mediating the stimulatory effects of EGF, whereas YY1 is a negative regulator of EAAT1 with HDACs as co-repressors, mediating the inhibitory effects of manganese on EAAT1 regulation.
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role of transcription factor yin yang 1 in manganese induced reduction of astrocytic Glutamate Transporters putative mechanism for manganese induced neurotoxicity
Neurochemistry International, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, James Johnson, Eun Sook LeeAbstract:Astrocytes are the most abundant non-neuronal glial cells in the brain. Once relegated to a mere supportive role for neurons, contemporary dogmas ascribe multiple active roles for these cells in central nervous system (CNS) function, including maintenance of optimal Glutamate levels in synapses. Regulation of Glutamate levels in the synaptic cleft is crucial for preventing excitotoxic neuronal injury. Glutamate levels are regulated predominantly by two astrocytic Glutamate Transporters, Glutamate Transporter 1 (GLT-1) and Glutamate Aspartate Transporter (GLAST). Indeed, the dysregulation of these Transporters has been linked to several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), as well as manganism, which is caused by overexposure to the trace metal, manganese (Mn). Although Mn is an essential trace element, its excessive accumulation in the brain as a result of chronic occupational or environmental exposures induces a neurological disorder referred to as manganism, which shares common pathological features with Parkinsonism. Mn decreases the expression and function of both GLAST and GLT-1. Astrocytes are commonly targeted by Mn, and thus reduction in astrocytic Glutamate Transporter function represents a critical mechanism of Mn-induced neurotoxicity. In this review, we will discuss the role of astrocytic Glutamate Transporters in neurodegenerative diseases and Mn-induced neurotoxicity.
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genetic dys regulation of astrocytic Glutamate Transporter eaat2 and its implications in neurological disorders and manganese toxicity
Neurochemical Research, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, James Johnson, Eun Sook LeeAbstract:Astrocytic Glutamate Transporters, the excitatory amino acid Transporter (EAAT) 2 and EAAT1 (Glutamate Transporter 1 and Glutamate Aspartate Transporter in rodents, respectively), are the main Transporters for maintaining optimal Glutamate levels in the synaptic clefts by taking up more than 90% of Glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these Transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these Transporters by various modes, such as single nucleotide polymorphisms and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via nuclear factor κB and cAMP response element binding protein at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics and translational regulation of EAAT2.
Youssef Sari - One of the best experts on this subject based on the ideXlab platform.
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β lactams modulate astroglial Glutamate Transporters and attenuate dependence to cp 55 940 a cb1 receptor agonist in rat model
Behavioural Brain Research, 2019Co-Authors: Alqassem Y Hakami, Fahad S Alshehri, Youssef SariAbstract:Abstract Studies on cannabinoids have reported contradictory findings, showing both aversion and rewarding outcomes in conditioned place preference (CPP). Various possibilities have been suggested to explain the aversive properties of cannabinoids, including the pharmacokinetics profile and dose selection. In this study, we have established a CPP method to investigate the effects of modulating astroglial Glutamate Transporters in cannabinoid dependence using a cannabinoid receptor 1 (CB1R) agonist, CP 55,940 (CP). Previous reports using CPP paradigm demonstrated the involvement of Glutamatergic system in seeking behavior of several drugs of abuse such as cocaine, heroin and nicotine. Glutamate homeostasis is maintained by several astroglial Glutamate Transporters, such as Glutamate Transporter 1 (GLT-1), cystine/Glutamate Transporter (xCT) and Glutamate Aspartate Transporter (GLAST). In this study, we investigated the effects of Ampicillin/Sulbactam, β-lactam compounds known to upregulate GLT-1 and xCT, on cannabinoid seeking behavior using CP. We found first that one prime dose of CP induced CP reinstatement; this effect was associated, in part, with significant downregulation of xCT expression in the nucleus accumbens, dorsomedial prefrontal cortex and amygdala. Moreover, GLT-1 expression was downregulated in the amygdala. Importantly, Ampicillin/Sulbactam treatment during the extinction phase attenuated CP-induced reinstatement and restored the expression of GLT-1 and xCT in mesocorticolimbic brain regions. These findings suggest that β-lactams may play a potential therapeutic role in attenuating dependence to cannabinoids, in part, through upregulation of GLT-1 and xCT.
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peri adolescent drinking of ethanol and or nicotine modulates astroglial Glutamate Transporters and metabotropic Glutamate receptor 1 in female alcohol preferring rats
Author, 2018Co-Authors: Fawaz Alasmari, Richard L Bell, P S S Rao, Alaa M Hammad, Youssef SariAbstract:Abstract Impairment in Glutamate neurotransmission mediates the development of dependence upon nicotine (NIC) and ethanol (EtOH). Previous work indicates that continuous access to EtOH or phasic exposure to NIC reduces expression of the Glutamate Transporter-1 (GLT-1) and cystine/Glutamate antiporter (xCT) but not the Glutamate/Aspartate Transporter (GLAST). Additionally, metabotropic Glutamate receptors (mGluRs) expression was affected following exposure to EtOH or NIC. However, little is known about the effects of EtOH and NIC co-consumption on GLT-1, xCT, GLAST, and mGluR1 expression. In this study, peri-adolescent female alcohol preferring (P) rats were given binge-like access to water, sucrose (SUC), SUC-NIC, EtOH, or EtOH-NIC for four weeks. The present study determined the effects of these reinforcers on GLT-1, xCT, GLAST, and mGluR1 expression in the nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC). GLT-1 and xCT expression were decreased in the NAc following both SUC-NIC and EtOH-NIC. In addition, only xCT expression was downregulated in the HIP in both of these latter groups. Also, glutathione peroxidase (GPx) activity in the HIP was reduced following SUC, SUC-NIC, EtOH, and EtOH-NIC consumption. Similar to previous work, GLAST expression was not altered in any brain region by any of the reinforcers. However, mGluR1 expression was increased in the NAc in the SUC-NIC, EtOH, and EtOH-NIC groups. These results indicate that peri-adolescent binge-like drinking of EtOH or SUC with or without NIC may exert differential effects on astroglial Glutamate Transporters and receptors. Our data further parallel some of the previous findings observed in adult rats.
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effects of chronic inhalation of electronic cigarettes containing nicotine on glial Glutamate Transporters and α 7 nicotinic acetylcholine receptor in female cd 1 mice
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2017Co-Authors: Fawaz Alasmari, Laura Crotty E Alexander, Jessica A Nelson, Isaac T Schiefer, Ellen C Breen, Christopher A Drummond, Youssef SariAbstract:Alteration in Glutamate neurotransmission has been found to mediate the development of drug dependence, including nicotine. We and others, through using western blotting, have reported that exposure to drugs of abuse reduced the expression of Glutamate Transporter-1 (GLT-1) as well as cystine/Glutamate antiporter (xCT), which consequently increased extracellular Glutamate concentrations in the mesocorticolimbic area. However, our previous studies did not reveal any changes in Glutamate/Aspartate Transporter (GLAST) following exposure to drugs of abuse. In the present study, for the first time, we investigated the effect of chronic exposure to electronic (e)-cigarette vapor containing nicotine, for one hour daily for six months, on GLT-1, xCT, and GLAST expression in frontal cortex (FC), striatum (STR), and hippocampus (HIP) in outbred female CD1 mice. In this study, we also investigated the expression of alpha-7 nicotinic acetylcholine receptor (α-7 nAChR), a major pre-synaptic nicotinic receptor in the Glutamatergic neurons, which regulates Glutamate release. We found that inhalation of e-cigarette vapor for six months increased α-7 nAChR expression in both FC and STR, but not in the HIP. In addition, chronic e-cigarette exposure reduced GLT-1 expression only in STR. Moreover, e-cigarette vapor inhalation induced downregulation of xCT in both the STR and HIP. We did not find any significant changes in GLAST expression in any brain region. Finally, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques, we detected high concentrations of nicotine and cotinine, a major metabolite of nicotine, in the FC tissues of e-cigarette exposed mice. These data provide novel evidence about the effects of chronic nicotine inhalation on the expression of key glial Glutamate Transporters as well as α-7 nAChR. Our work may suggest that nicotine exposure via chronic inhalation of e-cigarette vapor may be mediated in part by alterations in the Glutamatergic system.
Erika Sasaki - One of the best experts on this subject based on the ideXlab platform.
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Advance Access publication November 23, 2011 Abundant Occurrence of Basal Radial Glia in the Subventricular Zone of Embryonic Neocortex of a Lissencephalic Primate, the Common Marmoset Callithrix jacchus
2016Co-Authors: Iva Kelava, Isabel Reillo, Ayako Y. Murayama, Alex T. Kalinka, Denise Stenzel, Pavel Tomancak, Fumio Matsuzaki, Erika Sasaki, Jens C. Schwamborn, Hideyuki OkanoAbstract:Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of radial glial markers, and is capable of self-renewal. These progenitors, referred to here as basal radial glia (bRG), occur at high relative abundance in the SVZ of gyrencephalic primates (human) and nonprimates (ferret) but not lissencephalic rodents (mouse). Here, we analyzed the occurrence of bRG cells in the embryonic neocortex of the common marmoset Callithrix jacchus, a near-lissencephalic primate. bRG cells, expressing Pax6, Sox2 (but not Tbr2), Glutamate Aspartate Transporter, and glial fibrillary acidic protein and retaining a basal process at mitosis, occur a
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abundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate the common marmoset callithrix jacchus
Cerebral Cortex, 2012Co-Authors: Iva Kelava, Isabel Reillo, Alex T. Kalinka, Denise Stenzel, Pavel Tomancak, Fumio Matsuzaki, Erika Sasaki, Ayako Murayama, Cecile LebrandAbstract:Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of radial glial markers, and is capable of self-renewal. These progenitors, referred to here as basal radial glia (bRG), occur at high relative abundance in the SVZ of gyrencephalic primates (human) and nonprimates (ferret) but not lissencephalic rodents (mouse). Here, we analyzed the occurrence of bRG cells in the embryonic neocortex of the common marmoset Callithrix jacchus, a near-lissencephalic primate. bRG cells, expressing Pax6, Sox2 (but not Tbr2), Glutamate Aspartate Transporter, and glial fibrillary acidic protein and retaining a basal process at mitosis, occur at similar relative abundance in the marmoset SVZ as in human and ferret. The proportion of progenitors in M-phase was lower in embryonic marmoset than developing ferret neocortex, raising the possibility of a longer cell cycle. Fitting the gyrification indices of 26 anthropoid species to an evolutionary model suggested that the marmoset evolved from a gyrencephalic ancestor. Our results suggest that a high relative abundance of bRG cells may be necessary, but is not sufficient, for gyrencephaly and that the marmoset's lissencephaly evolved secondarily by changing progenitor parameters other than progenitor type.
Pratap Karki - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation of the astrocytic excitatory amino acid Transporter 1 eaat1 via nf κb and yin yang 1 yy1
Journal of Biological Chemistry, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, Clifford Kim, Deok Soo Son, Eun Sook LeeAbstract:Astrocytic Glutamate Transporter excitatory amino acid Transporter (EAAT) 1, also known as Glutamate Aspartate Transporter (GLAST) in rodents, is one of two glial Glutamate Transporters that are responsible for removing excess Glutamate from synaptic clefts to prevent excitotoxic neuronal death. Despite its important role in neurophysiological functions, the molecular mechanisms of EAAT1 regulation at the transcriptional level remain to be established. Here, we report that NF-κB is a main positive transcription factor for EAAT1, supported by the following: 1) EAAT1 contains two consensus sites for NF-κB, 2) mutation of NF-κB binding sites decreased EAAT1 promoter activity, and 3) activation of NF-κB increased, whereas inhibition of NF-κB decreased EAAT1 promoter activity and mRNA/protein levels. EGF increased EAAT1 mRNA/protein levels and Glutamate uptake via NF-κB. The transcription factor yin yang 1 (YY1) plays a role as a critical negative regulator of EAAT1, supported by the following: 1) the EAAT1 promoter contains multiple consensus sites for YY1, 2) overexpression of YY1 decreased EAAT1 promoter activity and mRNA/protein levels, and 3) knockdown of YY1 increased EAAT1 promoter activity and mRNA/protein levels. Manganese decreased EAAT1 expression via YY1. Epigenetic modifiers histone deacetylases (HDACs) served as co-repressors of YY1 to further decrease EAAT1 promoter activity, whereas inhibition of HDACs reversed manganese-induced decrease of EAAT1 expression. Taken together, our findings suggest that NF-κB is a critical positive regulator of EAAT1, mediating the stimulatory effects of EGF, whereas YY1 is a negative regulator of EAAT1 with HDACs as co-repressors, mediating the inhibitory effects of manganese on EAAT1 regulation.
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role of transcription factor yin yang 1 in manganese induced reduction of astrocytic Glutamate Transporters putative mechanism for manganese induced neurotoxicity
Neurochemistry International, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, James Johnson, Eun Sook LeeAbstract:Astrocytes are the most abundant non-neuronal glial cells in the brain. Once relegated to a mere supportive role for neurons, contemporary dogmas ascribe multiple active roles for these cells in central nervous system (CNS) function, including maintenance of optimal Glutamate levels in synapses. Regulation of Glutamate levels in the synaptic cleft is crucial for preventing excitotoxic neuronal injury. Glutamate levels are regulated predominantly by two astrocytic Glutamate Transporters, Glutamate Transporter 1 (GLT-1) and Glutamate Aspartate Transporter (GLAST). Indeed, the dysregulation of these Transporters has been linked to several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), as well as manganism, which is caused by overexposure to the trace metal, manganese (Mn). Although Mn is an essential trace element, its excessive accumulation in the brain as a result of chronic occupational or environmental exposures induces a neurological disorder referred to as manganism, which shares common pathological features with Parkinsonism. Mn decreases the expression and function of both GLAST and GLT-1. Astrocytes are commonly targeted by Mn, and thus reduction in astrocytic Glutamate Transporter function represents a critical mechanism of Mn-induced neurotoxicity. In this review, we will discuss the role of astrocytic Glutamate Transporters in neurodegenerative diseases and Mn-induced neurotoxicity.
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genetic dys regulation of astrocytic Glutamate Transporter eaat2 and its implications in neurological disorders and manganese toxicity
Neurochemical Research, 2015Co-Authors: Pratap Karki, Michael Aschner, Keisha Smith, James Johnson, Eun Sook LeeAbstract:Astrocytic Glutamate Transporters, the excitatory amino acid Transporter (EAAT) 2 and EAAT1 (Glutamate Transporter 1 and Glutamate Aspartate Transporter in rodents, respectively), are the main Transporters for maintaining optimal Glutamate levels in the synaptic clefts by taking up more than 90% of Glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these Transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these Transporters by various modes, such as single nucleotide polymorphisms and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via nuclear factor κB and cAMP response element binding protein at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics and translational regulation of EAAT2.