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Roles of CREB in the regulation of FMRP by group I metabotropic glutamate receptors in cingulate cortex

Hansen Wang1, Yoshikazu Morishita2, Daiki Miura2, Jose R Naranjo3, Satoshi Kida2 and Min Zhuo145*

Author Affiliations

1 Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

2 Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo, 156-8502, Japan

3 Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Científicas and Centro Investigaciones Biomedicas En Red-NEuroDegenerativas, E-28049, Madrid, Spain

4 Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, China

5 Department of Physiology, University of Toronto, Faculty of Medicine, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

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Molecular Brain 2012, 5:27  doi:10.1186/1756-6606-5-27

Published: 6 August 2012

Abstract

Background

Fragile X syndrome is caused by lack of fragile X mental retardation protein (FMRP) due to silencing of the FMR1 gene. The metabotropic glutamate receptors (mGluRs) in the central nervous system contribute to higher brain functions including learning/memory, mental disorders and persistent pain. The transcription factor cyclic AMP-responsive element binding protein (CREB) is involved in important neuronal functions, such as synaptic plasticity and neuronal survival. Our recent study has shown that stimulation of Group I mGluRs upregulated FMRP and activated CREB in anterior cingulate cortex (ACC), a key region for brain cognitive and executive functions, suggesting that activation of Group I mGluRs may upregulate FMRP through CREB signaling pathway.

Results

In this study, we demonstrate that CREB contributes to the regulation of FMRP by Group I mGluRs. In ACC neurons of adult mice overexpressing dominant active CREB mutant, the upregulation of FMRP by stimulating Group I mGluR is enhanced compared to wild-type mice. However, the regulation of FMRP by Group I mGluRs is not altered by overexpression of Ca2+-insensitive mutant form of downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor involved in synaptic transmission and plasticity.

Conclusion

Our study has provided further evidence for CREB involvement in regulation of FMRP by Group I mGluRs in ACC neurons, and may help to elucidate the pathogenesis of fragile X syndrome.

Keywords:
CREB; FMRP; Group I mGluRs; Gene expression; Cingulate cortex; Fragile X syndrome