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Mdm2 mediates FMRP- and Gp1 mGluR-dependent protein translation and neural network activity.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2017 Oct 15; Vol. 26 (20), pp. 3895-3908. - Publication Year :
- 2017
-
Abstract
- Activating Group 1 (Gp1) metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, elicits translation-dependent neural plasticity mechanisms that are crucial to animal behavior and circuit development. Dysregulated Gp1 mGluR signaling has been observed in numerous neurological and psychiatric disorders. However, the molecular pathways underlying Gp1 mGluR-dependent plasticity mechanisms are complex and have been elusive. In this study, we identified a novel mechanism through which Gp1 mGluR mediates protein translation and neural plasticity. Using a multi-electrode array (MEA) recording system, we showed that activating Gp1 mGluR elevates neural network activity, as demonstrated by increased spontaneous spike frequency and burst activity. Importantly, we validated that elevating neural network activity requires protein translation and is dependent on fragile X mental retardation protein (FMRP), the protein that is deficient in the most common inherited form of mental retardation and autism, fragile X syndrome (FXS). In an effort to determine the mechanism by which FMRP mediates protein translation and neural network activity, we demonstrated that a ubiquitin E3 ligase, murine double minute-2 (Mdm2), is required for Gp1 mGluR-induced translation and neural network activity. Our data showed that Mdm2 acts as a translation suppressor, and FMRP is required for its ubiquitination and down-regulation upon Gp1 mGluR activation. These data revealed a novel mechanism by which Gp1 mGluR and FMRP mediate protein translation and neural network activity, potentially through de-repressing Mdm2. Our results also introduce an alternative way for understanding altered protein translation and brain circuit excitability associated with Gp1 mGluR in neurological diseases such as FXS.<br /> (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Cell Culture Techniques
Down-Regulation
Hippocampus metabolism
Humans
Mice
Mice, Knockout
Nerve Net metabolism
Neurons metabolism
Rabbits
Receptor, Metabotropic Glutamate 5 metabolism
Signal Transduction
Fragile X Mental Retardation Protein metabolism
Nerve Net physiology
Proto-Oncogene Proteins c-mdm2 metabolism
Receptors, Metabotropic Glutamate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 26
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 29016848
- Full Text :
- https://doi.org/10.1093/hmg/ddx276