The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Sara H Rouhanifard - One of the best experts on this subject based on the ideXlab platform.
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visualizing adenosine to inosine rna editing in single mammalian cells
Nature Methods, 2017Co-Authors: Ian A Mellis, Rohit Gupte, Sara H RouhanifardAbstract:inoFISH uses fluorescence in situ hybridization to visualize and localize adenosine-to-inosine-edited transcripts. Conversion of adenosine to inosine is a frequent type of RNA editing, but important details about the biology of this conversion remain unknown because of a lack of imaging tools. We developed inoFISH to directly visualize and quantify adenosine-to-inosine-edited transcripts in situ. We found that editing of the GRIA2, EIF2AK2, and NUP43 transcripts is uncorrelated with nuclear localization and paraspeckle association. Further, NUP43 exhibits constant editing levels between single cells, while GRIA2 editing levels vary.
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visualizing adenosine to inosine rna editing in single mammalian cells
bioRxiv, 2016Co-Authors: Ian A Mellis, Rohit Gupte, Sara H RouhanifardAbstract:Conversion of adenosine bases to inosine in RNA is a frequent type of RNA editing, but important details about its biology, including subcellular localization, remain unknown due to a lack of imaging tools. We developed an RNA FISH strategy we called inoFISH that enables us to directly visualize and quantify adenosine-to-inosine edited transcripts in situ . Applying this tool to three edited transcripts (GRIA2, EIF2AK2 and NUP43), we found that editing of these transcripts is not correlated with nuclear localization nor paraspeckle association, and that NUP43 exhibits constant editing rates between single cells while the rates for GRIA2 vary.
Margaret T.t. Wong-riley - One of the best experts on this subject based on the ideXlab platform.
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Nuclear respiratory factor 2 regulates the transcription of AMPA receptor subunit GluA2 (GRIA2).
Biochimica et biophysica acta, 2014Co-Authors: Anusha Priya, Kaid Johar, Bindu Nair, Margaret T.t. Wong-rileyAbstract:Neuronal activity is highly dependent on energy metabolism. Nuclear respiratory factor 2 (NRF-2) tightly couples neuronal activity and energy metabolism by transcriptionally co-regulating all 13 subunits of an important energy-generating enzyme, cytochrome c oxidase (COX), as well as critical subunits of excitatory NMDA receptors. AMPA receptors are another major class of excitatory glutamatergic receptors that mediate most of the fast excitatory synaptic transmission in the brain. They are heterotetrameric proteins composed of various combinations of GluA1-4 subunits, with GluA2 being the most common one. We have previously shown that GluA2 (GRIA2) is transcriptionally regulated by nuclear respiratory factor 1 (NRF-1) and specificity protein 4 (Sp4), which also regulate all subunits of COX. However, it was not known if NRF-2 also couples neuronal activity and energy metabolism by regulating subunits of the AMPA receptors. By means of multiple approaches, including electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate the expression of GRIA2, but not of Gria1, Gria3, or Gria4 genes in neurons. By regulating the GluA2 subunit of the AMPA receptor, NRF-2 couples energy metabolism and neuronal activity at the transcriptional level through a concurrent and parallel mechanism with NRF-1 and Sp4.
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Specificity protein 4 (Sp4) regulates the transcription of AMPA receptor subunit GluA2 (GRIA2).
Biochimica et biophysica acta, 2014Co-Authors: Anusha Priya, Kaid Johar, Bindu Nair, Margaret T.t. Wong-rileyAbstract:The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are important glutamatergic receptors mediating fast excitatory synaptic transmission in the brain. The regulation of the four subunits of AMPA receptors, GluA1-4, is poorly understood. Excitatory synaptic transmission is highly energy-demanding, and this energy is derived mainly from the oxidative pathway. Recently, we found that specificity factor regulates all subunits of cytochrome c oxidase (COX), a critical energy-generating enzyme. COX is also regulated by nuclear respiratory factor 1 (NRF-1), which transcriptionally controls the GRIA2 (GluA2) gene of AMPA receptors. The goal of the present study was to test our hypothesis that Sp-factors (Sp1, Sp3, and/or Sp4) also regulate AMPA subunit genes. If so, we wish to determine if Sp-factors and NRF-1 function via a complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel mechanism. By means of multiple approaches, including electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutations, real-time quantitative PCR, and western blot analysis, we found that Sp4, but not Sp1 or Sp3, regulates the GRIA2, but not Gria1, 3, or 4, subunit gene of the AMPA receptor in a concurrent and parallel manner with NRF-1. Thus, Sp4 and NRF-1 both mediate the tight coupling between neuronal activity and energy metabolism at the transcriptional level.
Rolf Sprengel - One of the best experts on this subject based on the ideXlab platform.
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The GluA1 AMPAR subunit is necessary for hedonic responding but not hedonic value in female mice.
Physiology & behavior, 2020Co-Authors: Jasmin A. Strickland, Rolf Sprengel, Joseph M. Austen, David J. SandersonAbstract:Abstract The GluA1 subunit of the AMPA receptor has been implicated in anhedonia. Mice that lack GluA1 (Gria1 knockout mice) show reduced lick cluster size, a measure of palatability in feeding behaviour. This deficit may reflect a role for GluA1 in encoding the hedonic value of palatable substances or instead a role for GluA1 in the behavioural expression of hedonic value. We tested the role of GluA1 in hedonic value by assessing sensitivity to changes in the rewarding property of sucrose as a consequence of negative/positive contrast effects in female mice. During training, on half of the days consumption of a flavour (CS+) mixed with 4% sucrose was preceded by consumption of 1% sucrose (positive contrast). On the other half of days consumption of a different flavour (CS–) mixed with 4% sucrose was preceded by consumption of 16% sucrose (negative contrast). In the test session both wild-type, controls and Gria1 knockout mice consumed more of the CS+ flavour than the CS– flavour. While Gria1 knockout mice showed reduced lick cluster sizes, both genotypes made larger lick clusters for the CS+ flavour than the CS– flavour suggesting that the CS+ was more palatable than the CS–. A follow up experiment in normal mice demonstrated that the negative contrast procedure resulted in a conditioned reduction of palatability of the CS– in comparison to an associatively neutral, novel flavour. The results failed to demonstrate a role for GluA1 in hedonic value suggesting that, instead, GluA1 is necessary for hedonic responding.
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Hippocampal-prefrontal coherence mediates working memory and selective attention at distinct frequency bands and provides a causal link between schizophrenia and its risk gene GRIA1
Translational psychiatry, 2019Co-Authors: Alexei M. Bygrave, Rolf Sprengel, Thomas Jahans-price, Amy R. Wolff, Dimitri M. Kullmann, David M. Bannerman, Dennis KätzelAbstract:Increased fronto-temporal theta coherence and failure of its stimulus-specific modulation have been reported in schizophrenia, but the psychological correlates and underlying neural mechanisms remain elusive. Mice lacking the putative schizophrenia risk gene GRIA1 (Gria1-/-), which encodes GLUA1, show strongly impaired spatial working memory and elevated selective attention owing to a deficit in stimulus-specific short-term habituation. A failure of short-term habituation has been suggested to cause an aberrant assignment of salience and thereby psychosis in schizophrenia. We recorded hippocampal-prefrontal coherence while assessing spatial working memory and short-term habituation in these animals, wildtype (WT) controls, and Gria1-/- mice in which GLUA1 expression was restored in hippocampal subfields CA2 and CA3. We found that beta (20-30 Hz) and low-gamma (30-48 Hz) frequency coherence could predict working memory performance, whereas-surprisingly-theta (6-12 Hz) coherence was unrelated to performance and largely unaffected by genotype in this task. In contrast, in novel environments, theta coherence specifically tracked exploration-related attention in WT mice, but was strongly elevated and unmodulated in Gria1-knockouts, thereby correlating with impaired short-term habituation. Strikingly, reintroduction of GLUA1 selectively into CA2/CA3 restored abnormal short-term habituation, theta coherence, and hippocampal and prefrontal theta oscillations. Although local oscillations and coherence in other frequency bands (beta, gamma), and theta-gamma cross-frequency coupling also showed dependence on GLUA1, none of them correlated with short-term habituation. Therefore, sustained elevation of hippocampal-prefrontal theta coherence may underlie a failure in regulating novelty-related selective attention leading to aberrant salience, and thereby represents a mechanistic link between GRIA1 and schizophrenia.
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attenuation of novelty induced hyperactivity of gria1 mice by cannabidiol and hippocampal inhibitory chemogenetics
Frontiers in Pharmacology, 2019Co-Authors: Teemu Aittaaho, Milica Maksimovic, Kristiina Dahl, Rolf Sprengel, Esa R. KorpiAbstract:Gene-targeted mice with deficient AMPA receptor GluA1 subunits (Gria1-/- mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the Gria1-/- mice, while not affecting the wild-type littermate controls. Acute bilateral intra-dorsal hippocampal infusion of cannabidiol partially blocked the hyperactivity of the Gria1-/- mice, but had no effect on wild-types. The activation of the inhibitory DREADD receptor hM4Gi in the dorsal hippocampus by clozapine-N-oxide robustly inhibited the hyperactivity of the Gria1-/- mice, but had no effect on the locomotion of wild-type mice. Our results show that enhanced neuronal excitability in the hippocampus is associated with pronounced novelty-induced hyperactivity of GluA1 subunit-deficient mice. When this enhanced response of hippocampal neurons to novel stimuli is specifically reduced in the hippocampus by pharmacological treatment or by chemogenetic inhibition, Gria1-/- mice recover from behavioral hyperactivity, suggesting a hippocampal dysfunction in hyperactive behaviors that can be treated with cannabidiol.
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Data_Sheet_1_Attenuation of Novelty-Induced Hyperactivity of Gria1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics.PDF
2019Co-Authors: Teemu Aitta-aho, Milica Maksimovic, Kristiina Dahl, Rolf Sprengel, Esa R. KorpiAbstract:Gene-targeted mice with deficient AMPA receptor GluA1 subunits (Gria1-/- mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the Gria1-/- mice, while not affecting the wild-type littermate controls. Acute bilateral intra-dorsal hippocampal infusion of cannabidiol partially blocked the hyperactivity of the Gria1-/- mice, but had no effect on wild-types. The activation of the inhibitory DREADD receptor hM4Gi in the dorsal hippocampus by clozapine-N-oxide robustly inhibited the hyperactivity of the Gria1-/- mice, but had no effect on the locomotion of wild-type mice. Our results show that enhanced neuronal excitability in the hippocampus is associated with pronounced novelty-induced hyperactivity of GluA1 subunit-deficient mice. When this enhanced response of hippocampal neurons to novel stimuli is specifically reduced in the hippocampus by pharmacological treatment or by chemogenetic inhibition, Gria1-/- mice recover from behavioral hyperactivity, suggesting a hippocampal dysfunction in hyperactive behaviors that can be treated with cannabidiol.
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absent sleep eeg spindle activity in glua1 gria1 knockout mice relevance to neuropsychiatric disorders
Translational Psychiatry, 2018Co-Authors: G Ang, Rolf Sprengel, L E Mckillop, R J Purple, C Blancoduque, Stuart N Peirson, Russell G Foster, Paul J Harrison, Kay E Davies, Peter L OliverAbstract:Sleep EEG spindles have been implicated in attention, sensory processing, synaptic plasticity and memory consolidation. In humans, deficits in sleep spindles have been reported in a wide range of neurological and psychiatric disorders, including schizophrenia. Genome-wide association studies have suggested a link between schizophrenia and genes associated with synaptic plasticity, including the Gria1 gene which codes for the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Gria1−/− mice exhibit a phenotype relevant for neuropsychiatric disorders, including reduced synaptic plasticity and, at the behavioural level, attentional deficits leading to aberrant salience. In this study we report a striking reduction of EEG power density including the spindle-frequency range (10–15 Hz) during sleep in Gria1−/− mice. The reduction of spindle-activity in Gria1−/− mice was accompanied by longer REM sleep episodes, increased EEG slow-wave activity in the occipital derivation during baseline sleep, and a reduced rate of decline of EEG slow wave activity (0.5–4 Hz) during NREM sleep after sleep deprivation. These data provide a novel link between glutamatergic dysfunction and sleep abnormalities in a schizophrenia-relevant mouse model.
Ian A Mellis - One of the best experts on this subject based on the ideXlab platform.
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visualizing adenosine to inosine rna editing in single mammalian cells
Nature Methods, 2017Co-Authors: Ian A Mellis, Rohit Gupte, Sara H RouhanifardAbstract:inoFISH uses fluorescence in situ hybridization to visualize and localize adenosine-to-inosine-edited transcripts. Conversion of adenosine to inosine is a frequent type of RNA editing, but important details about the biology of this conversion remain unknown because of a lack of imaging tools. We developed inoFISH to directly visualize and quantify adenosine-to-inosine-edited transcripts in situ. We found that editing of the GRIA2, EIF2AK2, and NUP43 transcripts is uncorrelated with nuclear localization and paraspeckle association. Further, NUP43 exhibits constant editing levels between single cells, while GRIA2 editing levels vary.
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visualizing adenosine to inosine rna editing in single mammalian cells
bioRxiv, 2016Co-Authors: Ian A Mellis, Rohit Gupte, Sara H RouhanifardAbstract:Conversion of adenosine bases to inosine in RNA is a frequent type of RNA editing, but important details about its biology, including subcellular localization, remain unknown due to a lack of imaging tools. We developed an RNA FISH strategy we called inoFISH that enables us to directly visualize and quantify adenosine-to-inosine edited transcripts in situ . Applying this tool to three edited transcripts (GRIA2, EIF2AK2 and NUP43), we found that editing of these transcripts is not correlated with nuclear localization nor paraspeckle association, and that NUP43 exhibits constant editing rates between single cells while the rates for GRIA2 vary.
Anusha Priya - One of the best experts on this subject based on the ideXlab platform.
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Nuclear respiratory factor 2 regulates the transcription of AMPA receptor subunit GluA2 (GRIA2).
Biochimica et biophysica acta, 2014Co-Authors: Anusha Priya, Kaid Johar, Bindu Nair, Margaret T.t. Wong-rileyAbstract:Neuronal activity is highly dependent on energy metabolism. Nuclear respiratory factor 2 (NRF-2) tightly couples neuronal activity and energy metabolism by transcriptionally co-regulating all 13 subunits of an important energy-generating enzyme, cytochrome c oxidase (COX), as well as critical subunits of excitatory NMDA receptors. AMPA receptors are another major class of excitatory glutamatergic receptors that mediate most of the fast excitatory synaptic transmission in the brain. They are heterotetrameric proteins composed of various combinations of GluA1-4 subunits, with GluA2 being the most common one. We have previously shown that GluA2 (GRIA2) is transcriptionally regulated by nuclear respiratory factor 1 (NRF-1) and specificity protein 4 (Sp4), which also regulate all subunits of COX. However, it was not known if NRF-2 also couples neuronal activity and energy metabolism by regulating subunits of the AMPA receptors. By means of multiple approaches, including electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate the expression of GRIA2, but not of Gria1, Gria3, or Gria4 genes in neurons. By regulating the GluA2 subunit of the AMPA receptor, NRF-2 couples energy metabolism and neuronal activity at the transcriptional level through a concurrent and parallel mechanism with NRF-1 and Sp4.
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Specificity protein 4 (Sp4) regulates the transcription of AMPA receptor subunit GluA2 (GRIA2).
Biochimica et biophysica acta, 2014Co-Authors: Anusha Priya, Kaid Johar, Bindu Nair, Margaret T.t. Wong-rileyAbstract:The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are important glutamatergic receptors mediating fast excitatory synaptic transmission in the brain. The regulation of the four subunits of AMPA receptors, GluA1-4, is poorly understood. Excitatory synaptic transmission is highly energy-demanding, and this energy is derived mainly from the oxidative pathway. Recently, we found that specificity factor regulates all subunits of cytochrome c oxidase (COX), a critical energy-generating enzyme. COX is also regulated by nuclear respiratory factor 1 (NRF-1), which transcriptionally controls the GRIA2 (GluA2) gene of AMPA receptors. The goal of the present study was to test our hypothesis that Sp-factors (Sp1, Sp3, and/or Sp4) also regulate AMPA subunit genes. If so, we wish to determine if Sp-factors and NRF-1 function via a complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel mechanism. By means of multiple approaches, including electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutations, real-time quantitative PCR, and western blot analysis, we found that Sp4, but not Sp1 or Sp3, regulates the GRIA2, but not Gria1, 3, or 4, subunit gene of the AMPA receptor in a concurrent and parallel manner with NRF-1. Thus, Sp4 and NRF-1 both mediate the tight coupling between neuronal activity and energy metabolism at the transcriptional level.
