The Experts below are selected from a list of 1902 Experts worldwide ranked by ideXlab platform
Rolf Sprengel - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
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.
-
Attenuation of Novelty-Induced Hyperactivity of GRIA1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics.
Frontiers in pharmacology, 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.
-
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.
-
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.
Florian Freudenberg - One of the best experts on this subject based on the ideXlab platform.
-
quantitative analysis of GRIA1 gria2 dlg1 and dlg4 expression levels in hippocampus following forced swim stress in mice
Scientific Reports, 2019Co-Authors: Florian FreudenbergAbstract:AMPA receptors and interacting proteins are importantly involved in mediating stress-dependent plasticity. Previously we reported that GluA1-containing AMPA receptors and their interaction with PDZ-proteins are required for the experience-dependent expression of behavioral despair in the forced swim test. However, it is unclear if the expression of GluA1-containing AMPA receptors is affected by this type of behavior. Here we investigated in wild type mice, whether hippocampal gene or protein levels of GluA1 or associated PDZ proteins is altered following forced swim stress. We show that expression of Dlg4 (the gene coding for PSD-95) was strongly reduced after two days of forced swimming. In contrast, levels of Dlg1, GRIA1, and Gria2 (coding for SAP97, GluA1, and GluA2 respectively) were not affected after one or two days of forced swimming. The changes in gene expression largely did not translate to the protein level. These findings indicate a limited acute effect of forced swim stress on the expression of the investigated targets and suggest that the acute involvement of GluA1-containing AMPA receptors tor forced swim behavior is a result of non-genomic mechanisms.
-
hippocampal glua1 expression in GRIA1 mice only partially restores spatial memory performance deficits
Neurobiology of Learning and Memory, 2016Co-Authors: Florian Freudenberg, Rolf Sprengel, Evgeny Resnik, Alexander Kolleker, Tansu Celikel, Peter H. SeeburgAbstract:Spatial working memory (SWM) is an essential cognitive function important for survival in a competitive environment. In rodents SWM requires an intact hippocampus and SWM expression is impaired in mice lacking the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 (GRIA1-/- mice). Here we used viral gene transfer to show that re-expression of GluA1 in the hippocampus can affect the behavioral performance of GluA1 deficient mice. We found that GRIA1-/- mice with hippocampus-specific rescue of GluA1 expression (GRIA1Hpc mice) are more anxious, less hyperactive and only partly impaired in SWM expression in the Y-maze spatial novelty preference paradigm compared to GRIA1-/- mice. However, GRIA1Hpc mice still express SWM performance deficits when tested in the rewarded alternation T-maze task. Thus, the restoration of hippocampal function affects several behaviors of GluA1 deficient mice - including SWM expression - in different tasks. The virus-mediated GluA1 expression in GRIA1-/- mice is not sufficient for a comprehensive SWM restoration, suggesting that both hippocampal as well as extra-hippocampal GluA1-containing AMPA receptors contribute to SWM.
-
Hippocampal GluA1 expression in GRIA1(-/-) mice only partially restores spatial memory performance deficits
Neurobiology of learning and memory, 2016Co-Authors: Florian Freudenberg, Rolf Sprengel, Evgeny Resnik, Alexander Kolleker, Tansu Celikel, Peter H. SeeburgAbstract:Spatial working memory (SWM) is an essential cognitive function important for survival in a competitive environment. In rodents SWM requires an intact hippocampus and SWM expression is impaired in mice lacking the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 (GRIA1-/- mice). Here we used viral gene transfer to show that re-expression of GluA1 in the hippocampus can affect the behavioral performance of GluA1 deficient mice. We found that GRIA1-/- mice with hippocampus-specific rescue of GluA1 expression (GRIA1Hpc mice) are more anxious, less hyperactive and only partly impaired in SWM expression in the Y-maze spatial novelty preference paradigm compared to GRIA1-/- mice. However, GRIA1Hpc mice still express SWM performance deficits when tested in the rewarded alternation T-maze task. Thus, the restoration of hippocampal function affects several behaviors of GluA1 deficient mice - including SWM expression - in different tasks. The virus-mediated GluA1 expression in GRIA1-/- mice is not sufficient for a comprehensive SWM restoration, suggesting that both hippocampal as well as extra-hippocampal GluA1-containing AMPA receptors contribute to SWM.
-
Circuit mechanisms of GluA1‐dependent spatial working memory
Hippocampus, 2013Co-Authors: Florian Freudenberg, Rolf Sprengel, Peter H. Seeburg, Verena Marx, Tansu CelikelAbstract:Spatial working memory (SWM), the ability to process and manipulate spatial information over a relatively short period of time, requires an intact hippocampus, but also involves other forebrain nuclei in both in rodents and humans. Previous studies in mice showed that the molecular mechanism of SWM includes activation of AMPA receptors containing the GluA1 subunit (encoded by GRIA1) as GluA1 deletion in the whole brain (GRIA1(-/-) ) results in strong SWM deficit. However, since these mice globally lack GluA1, the circuit mechanisms of GluA1 contribution to SWM remain unknown. In this study, by targeted expression of GluA1 containing AMPA receptors in the forebrain of GRIA1(-/-) mice or by removing GluA1 selectively from hippocampus of mice with "floxed" GluA1 alleles (GRIA1(fl/fl) ), we show that SWM requires GluA1 action in cortical circuits but is only partially dependent on GluA1-containing AMPA receptors in hippocampus. We further show that hippocampal GluA1 contribution to SWM is temporally restricted and becomes prominent at longer retention intervals (>/=30 s). These findings provide a novel insight into the neural circuits required for SWM processing and argue that AMPA mediated signaling across forebrain and hippocampus differentially contribute to encoding of SWM. (c) 2013 Wiley Periodicals, Inc.
Peter H. Seeburg - One of the best experts on this subject based on the ideXlab platform.
-
Altered balance of excitatory and inhibitory learning in a genetically modified mouse model of glutamatergic dysfunction relevant to schizophrenia.
Scientific reports, 2017Co-Authors: David J. Sanderson, Rolf Sprengel, Peter H. Seeburg, Paul J Harrison, Aletheia Lee, David M. BannermanAbstract:The GluA1 AMPAR subunit (encoded by the GRIA1 gene) has been implicated in schizophrenia. GRIA1 knockout in mice results in recently experienced stimuli acquiring aberrantly high salience. This suggests that GluA1 may be important for learning that is sensitive to the temporal contiguity between events. To test this, mice were trained on a Pavlovian trace conditioning procedure in which the presentation of an auditory cue and food were separated by a temporal interval. Wild-type mice initially learnt, but with prolonged training came to withhold responding during the trace-conditioned cue, responding less than for another cue that was nonreinforced. GRIA1 knockout mice, in contrast, showed sustained performance over training, responding more to the trace-conditioned cue than the nonreinforced cue. Therefore, the trace-conditioned cue acquired inhibitory properties (signalling the absence of food) in wild-type mice, but GRIA1 deletion impaired the acquisition of inhibition, thus maintaining the stimulus as an excitatory predictor of food. Furthermore, when there was no trace both groups showed successful learning. These results suggest that cognitive abnormalities in disorders like schizophrenia in which gluatamatergic signalling is implicated may be caused by aberrant salience leading to a change in the nature of the information that is encoded.
-
The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice.
The European journal of neuroscience, 2017Co-Authors: Thomas Boerner, Rolf Sprengel, Peter H. Seeburg, Paul J Harrison, Alexei M. Bygrave, Jingkai Chen, Anushka Fernando, Stephanie Jackson, Chris Barkus, Gary GilmourAbstract:Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by GRIA1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in GRIA1-/- mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in GRIA1-/- mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.
-
hippocampal glua1 expression in GRIA1 mice only partially restores spatial memory performance deficits
Neurobiology of Learning and Memory, 2016Co-Authors: Florian Freudenberg, Rolf Sprengel, Evgeny Resnik, Alexander Kolleker, Tansu Celikel, Peter H. SeeburgAbstract:Spatial working memory (SWM) is an essential cognitive function important for survival in a competitive environment. In rodents SWM requires an intact hippocampus and SWM expression is impaired in mice lacking the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 (GRIA1-/- mice). Here we used viral gene transfer to show that re-expression of GluA1 in the hippocampus can affect the behavioral performance of GluA1 deficient mice. We found that GRIA1-/- mice with hippocampus-specific rescue of GluA1 expression (GRIA1Hpc mice) are more anxious, less hyperactive and only partly impaired in SWM expression in the Y-maze spatial novelty preference paradigm compared to GRIA1-/- mice. However, GRIA1Hpc mice still express SWM performance deficits when tested in the rewarded alternation T-maze task. Thus, the restoration of hippocampal function affects several behaviors of GluA1 deficient mice - including SWM expression - in different tasks. The virus-mediated GluA1 expression in GRIA1-/- mice is not sufficient for a comprehensive SWM restoration, suggesting that both hippocampal as well as extra-hippocampal GluA1-containing AMPA receptors contribute to SWM.
-
Hippocampal GluA1 expression in GRIA1(-/-) mice only partially restores spatial memory performance deficits
Neurobiology of learning and memory, 2016Co-Authors: Florian Freudenberg, Rolf Sprengel, Evgeny Resnik, Alexander Kolleker, Tansu Celikel, Peter H. SeeburgAbstract:Spatial working memory (SWM) is an essential cognitive function important for survival in a competitive environment. In rodents SWM requires an intact hippocampus and SWM expression is impaired in mice lacking the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 (GRIA1-/- mice). Here we used viral gene transfer to show that re-expression of GluA1 in the hippocampus can affect the behavioral performance of GluA1 deficient mice. We found that GRIA1-/- mice with hippocampus-specific rescue of GluA1 expression (GRIA1Hpc mice) are more anxious, less hyperactive and only partly impaired in SWM expression in the Y-maze spatial novelty preference paradigm compared to GRIA1-/- mice. However, GRIA1Hpc mice still express SWM performance deficits when tested in the rewarded alternation T-maze task. Thus, the restoration of hippocampal function affects several behaviors of GluA1 deficient mice - including SWM expression - in different tasks. The virus-mediated GluA1 expression in GRIA1-/- mice is not sufficient for a comprehensive SWM restoration, suggesting that both hippocampal as well as extra-hippocampal GluA1-containing AMPA receptors contribute to SWM.
-
Circuit mechanisms of GluA1‐dependent spatial working memory
Hippocampus, 2013Co-Authors: Florian Freudenberg, Rolf Sprengel, Peter H. Seeburg, Verena Marx, Tansu CelikelAbstract:Spatial working memory (SWM), the ability to process and manipulate spatial information over a relatively short period of time, requires an intact hippocampus, but also involves other forebrain nuclei in both in rodents and humans. Previous studies in mice showed that the molecular mechanism of SWM includes activation of AMPA receptors containing the GluA1 subunit (encoded by GRIA1) as GluA1 deletion in the whole brain (GRIA1(-/-) ) results in strong SWM deficit. However, since these mice globally lack GluA1, the circuit mechanisms of GluA1 contribution to SWM remain unknown. In this study, by targeted expression of GluA1 containing AMPA receptors in the forebrain of GRIA1(-/-) mice or by removing GluA1 selectively from hippocampus of mice with "floxed" GluA1 alleles (GRIA1(fl/fl) ), we show that SWM requires GluA1 action in cortical circuits but is only partially dependent on GluA1-containing AMPA receptors in hippocampus. We further show that hippocampal GluA1 contribution to SWM is temporally restricted and becomes prominent at longer retention intervals (>/=30 s). These findings provide a novel insight into the neural circuits required for SWM processing and argue that AMPA mediated signaling across forebrain and hippocampus differentially contribute to encoding of SWM. (c) 2013 Wiley Periodicals, Inc.
Tansu Celikel - One of the best experts on this subject based on the ideXlab platform.
-
hippocampal glua1 expression in GRIA1 mice only partially restores spatial memory performance deficits
Neurobiology of Learning and Memory, 2016Co-Authors: Florian Freudenberg, Rolf Sprengel, Evgeny Resnik, Alexander Kolleker, Tansu Celikel, Peter H. SeeburgAbstract:Spatial working memory (SWM) is an essential cognitive function important for survival in a competitive environment. In rodents SWM requires an intact hippocampus and SWM expression is impaired in mice lacking the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 (GRIA1-/- mice). Here we used viral gene transfer to show that re-expression of GluA1 in the hippocampus can affect the behavioral performance of GluA1 deficient mice. We found that GRIA1-/- mice with hippocampus-specific rescue of GluA1 expression (GRIA1Hpc mice) are more anxious, less hyperactive and only partly impaired in SWM expression in the Y-maze spatial novelty preference paradigm compared to GRIA1-/- mice. However, GRIA1Hpc mice still express SWM performance deficits when tested in the rewarded alternation T-maze task. Thus, the restoration of hippocampal function affects several behaviors of GluA1 deficient mice - including SWM expression - in different tasks. The virus-mediated GluA1 expression in GRIA1-/- mice is not sufficient for a comprehensive SWM restoration, suggesting that both hippocampal as well as extra-hippocampal GluA1-containing AMPA receptors contribute to SWM.
-
Hippocampal GluA1 expression in GRIA1(-/-) mice only partially restores spatial memory performance deficits
Neurobiology of learning and memory, 2016Co-Authors: Florian Freudenberg, Rolf Sprengel, Evgeny Resnik, Alexander Kolleker, Tansu Celikel, Peter H. SeeburgAbstract:Spatial working memory (SWM) is an essential cognitive function important for survival in a competitive environment. In rodents SWM requires an intact hippocampus and SWM expression is impaired in mice lacking the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 (GRIA1-/- mice). Here we used viral gene transfer to show that re-expression of GluA1 in the hippocampus can affect the behavioral performance of GluA1 deficient mice. We found that GRIA1-/- mice with hippocampus-specific rescue of GluA1 expression (GRIA1Hpc mice) are more anxious, less hyperactive and only partly impaired in SWM expression in the Y-maze spatial novelty preference paradigm compared to GRIA1-/- mice. However, GRIA1Hpc mice still express SWM performance deficits when tested in the rewarded alternation T-maze task. Thus, the restoration of hippocampal function affects several behaviors of GluA1 deficient mice - including SWM expression - in different tasks. The virus-mediated GluA1 expression in GRIA1-/- mice is not sufficient for a comprehensive SWM restoration, suggesting that both hippocampal as well as extra-hippocampal GluA1-containing AMPA receptors contribute to SWM.
-
Circuit mechanisms of GluA1‐dependent spatial working memory
Hippocampus, 2013Co-Authors: Florian Freudenberg, Rolf Sprengel, Peter H. Seeburg, Verena Marx, Tansu CelikelAbstract:Spatial working memory (SWM), the ability to process and manipulate spatial information over a relatively short period of time, requires an intact hippocampus, but also involves other forebrain nuclei in both in rodents and humans. Previous studies in mice showed that the molecular mechanism of SWM includes activation of AMPA receptors containing the GluA1 subunit (encoded by GRIA1) as GluA1 deletion in the whole brain (GRIA1(-/-) ) results in strong SWM deficit. However, since these mice globally lack GluA1, the circuit mechanisms of GluA1 contribution to SWM remain unknown. In this study, by targeted expression of GluA1 containing AMPA receptors in the forebrain of GRIA1(-/-) mice or by removing GluA1 selectively from hippocampus of mice with "floxed" GluA1 alleles (GRIA1(fl/fl) ), we show that SWM requires GluA1 action in cortical circuits but is only partially dependent on GluA1-containing AMPA receptors in hippocampus. We further show that hippocampal GluA1 contribution to SWM is temporally restricted and becomes prominent at longer retention intervals (>/=30 s). These findings provide a novel insight into the neural circuits required for SWM processing and argue that AMPA mediated signaling across forebrain and hippocampus differentially contribute to encoding of SWM. (c) 2013 Wiley Periodicals, Inc.
Esa R. Korpi - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
Attenuation of Novelty-Induced Hyperactivity of GRIA1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics.
Frontiers in pharmacology, 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.
-
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.
-
Reversal of novelty-induced hippocampal c-Fos expression in GluA1 subunit-deficient mice by chronic treatment targeting glutamatergic transmission
European journal of pharmacology, 2014Co-Authors: Milica Maksimovic, Teemu Aitta-aho, Esa R. KorpiAbstract:Malfunction of glutamate transmission is implicated in several neuropsychiatric disorders. GRIA1-/- mouse line with knocked-out GluA1 subunits of ionotropic AMPA glutamate receptor displays several behavioural features of schizoaffective disorder. Typically, these mice show hyperactivity provoked by environmental novelty, which is attenuated after 4-week treatment with the standard mood-stabilisers lithium and valproate and the mood-stabilising anticonvulsants topiramate and lamotrigine (Maksimovic, M., Vekovischeva, O.Y., Aitta-Aho, T., Korpi, E.R., 2014. Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice. PloS One. 9, e100188). Here, we complement our study by treating these mice chronically with perampanel, a novel non-competitive antagonist of AMPA receptors, for 4 weeks at the dose of 60 mg/kg diet, and found reduced locomotor hyperactivity in the GRIA1-/- animals, while not affecting the wild-type littermates. To study the cellular mechanism by which chronic treatments with glutamate-modulating mood-stabilizing drugs alleviate this hyperactivity, we used the immediate early gene c-Fos protein expression as a marker of neuronal activity in the brain. Chronic lithium, valproate and topiramate blunted the c-Fos expression especially in the dorsal hippocampus of the GRIA1-/- mice, with all of them reducing the number of c-Fos-positive cells in the CA3 region and valproate and topiramate also in the dentate gyrus (DG). Lamotrigine and perampanel treatments had the same effect in the all CA1, CA3 and DG subfields of the dorsal hippocampus of GRIA1-/- mice. The results suggest that abnormal (hippocampal) glutamatergic transmission underlies the hyperactive phenotype of the GRIA1-/- mice in a novel environment, and based on the efficacies of the present chronic drug treatments, this mouse model may serve as a predictive tool for studying novel mood-stabilisers.
-
Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice.
PloS one, 2014Co-Authors: Milica Maksimovic, Olga Y. Vekovischeva, Teemu Aitta-aho, Esa R. KorpiAbstract:Abnormal excitatory glutamate neurotransmission and plasticity have been implicated in schizophrenia and affective disorders. GRIA1−/− mice lacking GluA1 subunit (encoded by GRIA1 gene) of AMPA-type glutamate receptor show robust novelty-induced hyperactivity, social deficits and heightened approach features, suggesting that they could be used to test for anti-manic activity of drugs. Here, we tested the efficacy of chronic treatment with established anti-manic drugs on behavioural properties of the GRIA1−/− mice. The mice received standard mood stabilizers (lithium and valproate) and novel ones (topiramate and lamotrigine, used more as anticonvulsants) as supplements in rodent chow for at least 4 weeks. All drugs attenuated novelty-induced locomotor hyperactivity of the GRIA1−/− mice, especially by promoting the habituation, while none of them attenuated 2-mg/kg amphetamine-induced hyperactivity as compared to control diet. Treatment with lithium and valproate reversed the elevated exploratory activity of GRIA1−/− mice. Valproate treatment also reduced struggling behaviour in tail suspension test and restored reciprocally-initiated social contacts of GRIA1−/− mice to the level shown by the wild-type GRIA1+/+ mice. GRIA1−/− mice consumed slightly more sucrose during intermittent sucrose exposure than the wild-types, but ran similar distances on running wheels. These behaviours were not consistently affected by lithium and valproate in the GRIA1−/− mice. The efficacy of various anti-manic drug treatments on novelty-induced hyperactivity suggests that the GRIA1−/− mouse line can be utilized in screening for new therapeutics.
