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Extracellular cGMP Reverses Altered Membrane Expression of AMPA Receptors in Hippocampus of Hyperammonemic Rats: Underlying Mechanisms

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Abstract

Chronic hyperammonemia impairs spatial memory by altering membrane expression of GluA1 and GluA2 subunits of AMPA receptors in hippocampus. Intracerebral administration of extracellular cGMP to hyperammonemic rats restores spatial memory and membrane expression of AMPA receptors. The underlying molecular mechanisms remain unknown and cannot be analyzed in vivo. The aims of the present work were to (1) assess whether extracellular cGMP reverses the alterations in membrane expression of GluA1 and GluA2 in hippocampus of hyperammonemic rats ex vivo and (2) identify the underlying mechanisms. To reach these aims, we used freshly isolated hippocampal slices from control and hyperammonemic rats and treated them ex vivo with extracellular cGMP. Extracellular cGMP normalizes membrane expression of GluA2 restoring its phosphorylation in Ser880 because it restores PKCζ activation by Thr560 auto-phosphorylation, which is a consequence of normalization by extracellular cGMP of phosphorylation and activity of p38 which was increased in hyperammonemic rats. Normalization of p38 is a consequence of normalization of membrane expression of the GluN2B subunit of NMDA receptor, mediated by a reduction in its phosphorylation in Tyr1472 due to reduction of Src activation, which was over-activated in hyperammonemic rats. Extracellular cGMP also restores membrane expression of GluA1 increasing its phosphorylation at Ser831 because it restores CaMKII membrane association and phosphorylation in Thr286. All these effects of extracellular cGMP are due to a reduction of hippocampal IL-1β levels in hyperammonemic rats, which reduces IL-1 receptor-mediated Src over-activation. Reduction in IL-1β levels is due to the reduction of microglia activation in hippocampus of hyperammonemic rats.

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Funding

Ministerio de Ciencia e Innovación Spain (SAF2014-51851-R and SAF2017-82917-R), Consellería Educación Generalitat Valenciana (PROMETEOII/2014/033), co-funded with European Regional Development Funds (ERDF); Ministerio de Educación, Cultura y Deporte (FPU13/02492).

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Authors and Affiliations

  1. Laboratory of Neurobiology, Centro de Investigacion Pincipe Felipe, Valencia, Spain

    Lucas Taoro-Gonzalez, Yaiza M. Arenas, Andrea Cabrera-Pastor & Vicente Felipo

  2. Fundacion Investigacion Hospital Clinico, Instituto Investigacion Sanitaria-INCLIVA, Valencia, Spain

    Andrea Cabrera-Pastor

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  1. Lucas Taoro-Gonzalez
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  2. Yaiza M. Arenas
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  3. Andrea Cabrera-Pastor
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  4. Vicente Felipo
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Contributions

LTG: most ex vivo experiments with fresh slices, membrane expression experiments and western blot analysis; LTG and ACP: analysis and interpretation of data, drafting of the manuscript; YMA: immunohistochemical studies and analysis; ACP and VF: study concept, design and supervision, analysis and interpretation of data; VF: obtained funding, writing of the manuscript.

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Correspondence to Vicente Felipo.

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Taoro-Gonzalez, L., Arenas, Y.M., Cabrera-Pastor, A. et al. Extracellular cGMP Reverses Altered Membrane Expression of AMPA Receptors in Hippocampus of Hyperammonemic Rats: Underlying Mechanisms. Mol Neurobiol 56, 4428–4439 (2019). https://doi.org/10.1007/s12035-018-1387-z

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