C²⁺/calmodulin-dependent protein kinase IV links group I metabotropic glutamate receptors to fragile X mental retardation protein in cingulate cortex

Fragile X syndrome is caused by a 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, persistent pain, and mental disorders. Our recent study has shown that activation of Group I mGluR upregulated FMRP in anterior cingulate cortex (ACC), a key region for brain cognitive and executive functions; Ca²⁺ signaling pathways could be involved in the regulation of FMRP by Group I mGluRs. In this study we demonstrate that stimulating Group I mGluRs activates Ca²⁺/calmodulin-dependent protein kinase IV (CaMKIV) in ACC neurons. In ACC neurons of adult mice overexpressing CaMKIV, the up-regulation of FMRP by stimulating Group I mGluR is enhanced. The enhancement occurs at the transcriptional level as the Fmr1 mRNA level was further elevated compared with wild-type mice. Using pharmacological approaches, we found that inhibition of CaMKIV could attenuate the up-regulation of FMRP by Group I mGluRs. CaMKIV contribute to the regulation of FMRP by Group I mGluRs probably through cyclic AMP-responsive element binding protein (CREB) activation, as manipulation of CaMKIV could simultaneously cause the change of CREB phosphorylation induced by Group I mGluR activation. Our study has provided strong evidence for CaMKIV as a molecular link between Group I mGluRs and FMRP in ACC neurons and may help us to elucidate the pathogenesis of fragile X syndrome.