Chronic hyperammonemia alters in opposite ways membrane expression of GluA1 and GluA2 AMPA receptor subunits in cerebellum. Molecular mechanisms involved

Cabrera‐Pastor, Andrea; Taoro‐González, Lucas; López-Merino, Esperanza; Celma, Ferran; Llansola, Marta; Felipo, Vicente

doi:10.1016/j.bbadis.2017.10.031

Cited by 10 publications

(6 citation statements)

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“…The ammonium-containing diet was prepared as described in [33] (but using 25% ammonium acetate) and increased blood ammonia levels around threefold, an increase similar to that found in patients with liver cirrhosis. Rats remain hyperammonemic for long periods of time and reproduce many cognitive and motor alterations present in cirrhotic patients with hepatic encephalopathy and has allowed identifying some underlying mechanisms [7][8][9][34][35][36]. Experiments were performed after 4-5 weeks in the ammonium diet, when the rats are 10-11 weeks old.…”

Section: Model Of Chronic Hyperammonemiamentioning

confidence: 99%

Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of ampa receptors in hippocampus by enhancing activation of the il-1 receptor: underlying mechanisms

Taoro‐González¹

2018

Preprint

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Background: Hyperammonemic rats reproduce the cognitive alterations of patients with hepatic encephalopathy, including altered spatial memory, attributed to altered membrane expression of AMPA receptor subunits in hippocampus. Neuroinflammation mediates these cognitive alterations. We hypothesized that hyperammonemia-induced increase in IL-1β in hippocampus would be responsible for the altered GluA1 and GluA2 membrane expression. The aims of this work were to (1) assess if increased IL-1β levels and activation of its receptor are responsible for the changes in GluA1 and/or GluA2 membrane expression in hyperammonemia and (2) identify the mechanisms by which activation of IL-1 receptor leads to altered membrane expression of GluA1 and GluA2. Methods: We analyzed in hippocampal slices from control and hyperammonemic rat membrane expression of AMPA receptors using the BS3 cross-linker and phosphorylation of the GluA1 and GluA2 subunits using phosphor-specific antibodies. The IL-1 receptor was blocked with IL-Ra, and the signal transduction pathways involved in modulation of membrane expression of GluA1 and GluA2 were analyzed using inhibitors of key steps. Results: Hyperammonemia reduces GluA1 and increases GluA2 membrane expression and reduces phosphorylation of GluA1 at Ser831 and of GluA2 at Ser880. Hyperammonemia increases IL-1β, enhancing activation of IL-1 receptor. This leads to activation of Src. The changes in membrane expression of GluA1 and GluA2 are reversed by blocking the IL-1 receptor with IL-1Ra or by inhibiting Src with PP2. After Src activation, the pathways for GluA2 and GluA1 diverge. Src increases phosphorylation of GluN2B at Tyr14721 and membrane expression of GluN2B in hyperammonemic rats, leading to activation of MAP kinase p38, which binds to and reduces phosphorylation at Thr560 and activity of PKCζ, resulting in reduced phosphorylation at Ser880 and enhanced membrane expression of GluA2. Increased Src activity in hyperammonemic rats also activates PKCδ which enhances phosphorylation of GluN2B at Ser1303, reducing membrane expression of CaMKII and phosphorylation at Ser831 and membrane expression of GluA1. Conclusions: This work identifies two pathways by which neuroinflammation alters glutamatergic neurotransmission in hippocampus. The steps of the pathways identified could be targets to normalize neurotransmission in hyperammonemia and other pathologies associated with increased IL-1β by acting, for example, on p38 or PKCδ.

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Section: Model Of Chronic Hyperammonemiamentioning

confidence: 99%

Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of ampa receptors in hippocampus by enhancing activation of the il-1 receptor: underlying mechanisms

Taoro‐González¹

2018

Preprint

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“…The mechanism by which hyperammonemia increases PKC activity in the cerebellum has been already described and is mediated by increased activity of CaMKII which in turn, indirectly, enhances PKC activity [ 2 ]. Increased activity of CaMKII in hyperammonemia is due to increased phosphorylation at the residue Thr286, which is biphasically modulated by calcium concentration [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Rats with chronic hyperammonemia reproduce the cognitive impairment and motor in-coordination shown by cirrhotic patients with minimal hepatic encephalopathy and are a good model to identify the underlying mechanisms and to test treatments to improve them. Chronic hyperammonemia induces neuroinflammation which alters glutamatergic and GABAergic neurotransmission in cerebellum and hippocampus leading to cognitive and motor impairment [1][2][3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Blocking glycine receptors reduces neuroinflammation and restores neurotransmission in cerebellum through ADAM17-TNFR1-NF-κβ pathway

Arenas

Cabrera‐Pastor

Juciute

et al. 2020

J Neuroinflammation

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Background Chronic hyperammonemia induces neuroinflammation in cerebellum, with glial activation and enhanced activation of the TNFR1-NF-kB-glutaminase-glutamate-GABA pathway. Hyperammonemia also increases glycinergic neurotransmission. These alterations contribute to cognitive and motor impairment. Activation of glycine receptors is reduced by extracellular cGMP, which levels are reduced in cerebellum of hyperammonemic rats in vivo. We hypothesized that enhanced glycinergic neurotransmission in hyperammonemic rats (1) contributes to induce neuroinflammation and glutamatergic and GABAergic neurotransmission alterations; (2) is a consequence of the reduced extracellular cGMP levels. The aims were to assess, in cerebellum of hyperammonemic rats, (a) whether blocking glycine receptors with the antagonist strychnine reduces neuroinflammation; (b) the cellular localization of glycine receptor; (c) the effects of blocking glycine receptors on the TNFR1-NF-kB-glutaminase-glutamate-GABA pathway and microglia activation; (d) whether adding extracellular cGMP reproduces the effects of strychnine. Methods We analyzed in freshly isolated cerebellar slices from control or hyperammonemic rats the effects of strychnine on activation of microglia and astrocytes, the content of TNFa and IL1b, the surface expression of ADAM17, TNFR1 and transporters, the phosphorylation levels of ERK, p38 and ADAM17. The cellular localization of glycine receptor was assessed by immunofluorescence. We analyzed the content of TNFa, IL1b, HMGB1, glutaminase, and the level of TNF-a mRNA and NF-κB in Purkinje neurons. Extracellular concentrations of glutamate and GABA were performed by in vivo microdialysis in cerebellum. We tested whether extracellular cGMP reproduces the effects of strychnine in ex vivo cerebellar slices. Results Glycine receptors are expressed mainly in Purkinje cells. In hyperammonemic rats, enhanced glycinergic neurotransmission leads to reduced membrane expression of ADAM17, resulting in increased surface expression and activation of TNFR1 and of the associated NF-kB pathway. This increases the expression in Purkinje neurons of TNFa, IL-1b, HMGB1, and glutaminase. Increased glutaminase activity leads to increased extracellular glutamate, which increases extracellular GABA. Increased extracellular glutamate and HMGB1 potentiate microglial activation. Blocking glycine receptors with strychnine or extracellular cGMP completely prevents the above pathway in hyperammonemic rats. Conclusions Glycinergic neurotransmission modulates neuroinflammation. Enhanced glycinergic neurotransmission in hyperammonemia would be due to reduced extracellular cGMP. These results shed some light on possible new therapeutic target pathways for pathologies associated to neuroinflammation.

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“…Several reports have shown that rats with chronic hyperammonemia show neuroinflammation in cerebellum and hippocampus, which alters GABAergic and glutamatergic neurotransmission leading to impairment of motor coordination and of spatial and non‐spatial learning and memory (Cabrera‐Pastor et al, ; Cauli eta al., ; Hernández‐Rabaza, Cabrera‐Pastor, Taoro‐Gonzalez, Agusti et al, ; Hernández‐Rabaza, Cabrera‐Pastor, Taoro‐Gonzalez, Malaguarnera ; Taoro‐Gonzalez et al, ). Some of these reports have identified in detail the pathways by which neuroinflammation alters different aspects of neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in animal models have shown that chronic moderate hyperammonemia (HA), similar to that present in cirrhotic patients, is enough to alter cognitive and motor function, because of altered glutamatergic and GABAergic neurotransmission, which, in turn, is because of neuroinflammation (Cabrera‐Pastor et al, ; Cauli et al, ; Hernández‐Rabaza, Cabrera‐Pastor, Taoro‐Gonzalez, Agusti et al, ; Hernández‐Rabaza, Cabrera‐Pastor, Taoro‐Gonzalez, Malaguarnera ; Llansola et al, ; Rodrigo et al, ; Taoro‐González, Arenas, Cabrera‐Pastor, & Felipo, ). Treatment with ibuprofen reduces neuroinflammation in hyperammonemic rats and improves cognitive and motor function (Rodrigo et al, ).…”

Section: Introductionmentioning

confidence: 99%

Hyperammonemia alters the mismatch negativity in the auditory evoked potential by altering functional connectivity and neurotransmission

García‐García

Guerrero

Lavilla‐Miyasato

et al. 2020

Journal of Neurochemistry

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Minimal hepatic encephalopathy (MHE) is a neuropsychiatric syndrome produced by central nervous system dysfunction subsequent to liver disease. Hyperammonemia and inflammation act synergistically to alter neurotransmission, leading to the cognitive and motor alterations in MHE, which are reproduced in rat models of chronic hyperammonemia. Patients with MHE show altered functional connectivity in different neural networks and a reduced response in the cognitive potential mismatch negativity (MMN), which correlates with attention deficits. The mechanisms by which MMN is altered in MHE remain unknown. The objectives of this work are as follows: To assess if rats with chronic hyperammonemia reproduce the reduced response in the MMN found in patients with MHE. Analyze the functional connectivity between the areas (CA1 area of the dorsal hippocampus, prelimbic cortex, primary auditory cortex, and central inferior colliculus) involved in the generation of the MMN and its possible alterations in hyperammonemia. Granger causality analysis has been applied to detect the net flow of information between the population neuronal activities recorded from a local field potential approach. Analyze if altered MMN response in hyperammonemia is associated with alterations in glutamatergic and GABAergic neurotransmission. Extracellular levels of the neurotransmitters and/or membrane expression of their receptors have been analyzed after the tissue isolation of the four target sites. The results show that rats with chronic hyperammonemia show reduced MMN response in hippocampus, mimicking the reduced MMN response of patients with MHE. This is associated with altered functional connectivity between the areas involved in the generation of the MMN. Hyperammonemia also alters membrane expression of glutamate and GABA receptors in hippocampus and reduces the changes in extracellular GABA and glutamate induced by the MMN paradigm of auditory stimulus in hippocampus of control rats. The changes in glutamatergic and GABAergic neurotransmission and in functional connectivity between the brain areas analyzed would contribute to the impairment of the MMN response in rats with hyperammonemia and, likely, also in patients with MHE.

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Chronic hyperammonemia alters in opposite ways membrane expression of GluA1 and GluA2 AMPA receptor subunits in cerebellum. Molecular mechanisms involved

Cited by 10 publications

References 50 publications

Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of ampa receptors in hippocampus by enhancing activation of the il-1 receptor: underlying mechanisms

Hyperammonemia alters membrane expression of GluA1 and GluA2 subunits of ampa receptors in hippocampus by enhancing activation of the il-1 receptor: underlying mechanisms

Blocking glycine receptors reduces neuroinflammation and restores neurotransmission in cerebellum through ADAM17-TNFR1-NF-κβ pathway

Hyperammonemia alters the mismatch negativity in the auditory evoked potential by altering functional connectivity and neurotransmission

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