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The Journal of Neuroscience, April 23, 2008, 28(17):4385-4397; doi:10.1523/JNEUROSCI.0646-08.2008

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Neurobiology of Disease
Roles of Calcium-Stimulated Adenylyl Cyclase and Calmodulin-Dependent Protein Kinase IV in the Regulation of FMRP by Group I Metabotropic Glutamate Receptors

Hansen Wang, Long-Jun Wu, Fuxing Zhang, and Min Zhuo

Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Correspondence should be addressed to Dr. Min Zhuo, Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Email: min.zhuo{at}utoronto.ca

The fragile X syndrome is caused by the lack of fragile X mental retardation protein (FMRP) attributable to silencing of the FMR1 gene. The metabotropic glutamate receptors (mGluRs) in the CNS contribute to different brain functions, including learning/memory, mental disorders, drug addiction, and persistent pain. Most of the previous studies have been focused on downstream targets of FMRP in hippocampal neurons, and fewer studies have been reported for the second-messenger signaling pathways between group I mGluRs and FMRP. Furthermore, no molecular study has been performed in the anterior cingulate cortex (ACC), a key region involved in high brain cognitive and executive functions. In this study, we demonstrate that activation of group I mGluR upregulated FMRP in ACC neurons of adult mice through the Ca²⁺-dependent signaling pathways. Using genetic approaches, we found that Ca²⁺/calmodulin-stimulated adenylyl cyclase 1 (AC1) and calcium/calmodulin-dependent kinase IV (CaMKIV) contribute to the upregulation of FMRP induced by stimulating group I mGluRs. The upregulation of FMRP occurs at the transcriptional level. The cAMP-dependent protein kinase is activated by stimulating group I mGluRs through AC1 in ACC neurons. Both AC1 and CaMKIV contribute to the regulation of FMRP by group I mGluRs probably through cAMP response element-binding protein activation. Our study has provided the first evidence for a molecular link between group I mGluRs and FMRP in ACC neurons and may help us to understand the pathogenesis of fragile X syndrome.

Key words: adenylyl cyclase 1; CaMKIV; CREB; FMRP; group I mGluRs; cingulate cortex

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Received Nov. 15, 2007; revised March 19, 2008; accepted March 21, 2008.

Correspondence should be addressed to Dr. Min Zhuo, Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Email: min.zhuo{at}utoronto.ca

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