Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression

Abstract

Genetic deletion of fragile X mental retardation protein (FMRP) has been shown to enhance mGluR-dependent long-term depression (LTD). Herein, we demonstrate that mGluR-LTD induces a transient, translation-dependent increase in FMRP that is rapidly degraded by the ubiquitin-proteasome pathway. Moreover, proteasome inhibitors abolished mGluR-LTD, and LTD was absent in mice that overexpress human FMRP. Neither translation nor proteasome inhibitors blocked the augmentation of mGluR-LTD in FMRP-deficient mice. In addition, mGluR-LTD is associated with rapid increases in the protein levels of FMRP target mRNAs in wild-type mice. Interestingly, the basal levels of these proteins were elevated and their synthesis was improperly regulated during mGluR-LTD in FMRP-deficient mice. Our findings indicate that hippocampal mGluR-LTD requires the rapid synthesis and degradation of FMRP and that mGluR-LTD triggers the synthesis of FMRP binding mRNAs. These findings indicate that the translation, ubiquitination, and proteolysis of FMRP functions as a dynamic regulatory system for controlling synaptic plasticity.

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…Hence, Bear et al (2004) proposed that mGlu 1/5 signaling might be a promising therapeutic target for FXS. Follow-up studies further demonstrated that, in contrast to wild-type, mGlu 1/5 LTD is protein synthesisindependent in Fmr1 KO mice (Nosyreva and Huber, 2006;Hou et al, 2006), thus corroborating the assumption that a major regulator of neuronal protein synthesis is lost in FXS.…”

“…The most prominent and best-studied example is hippocampal metabotropic glutamate receptor 1/5 (mGlu 1/5 )-dependent synaptic long-term depression (LTD), which is exaggerated and, in contrast to wild type, protein synthesis independent in Fmr1 KO hippocampus Nosyreva and Huber, 2006;Hou et al, 2006; further discussed below). Several studies have also shown impaired long-term potentiation (LTP) in different cortical areas of Fmr1 KO mice Zhao et al, 2005;Desai et al, 2006).…”

Advances in behavioral genetics: mouse models of autism

“…84 Synaptic dysregulation in genetic mouse models for autism Although the mouse model for FXS does not fully recapitulate the behavioral phenotype of the clinical disease, there are very interesting symmetries between findings of abnormal dendritic spine morphology, including alterations in length and density, in brain of human patients and in Fmr1-null mice. 101,102 Further work has shown that Fmrp loss has marked effects on measures of synaptic plasticity in mutant mice, with significant enhancement of mGluR (group 1 metabotropic glutamate receptor) dependent long-term depression (LTD) in hippocampus, [103][104][105] and decreased cortical long-term potentiation (LTP). 106,107 The molecular mechanisms underlying these changes have yet to be elucidated, but are thought to be related to the role of FMRP in mRNA transport and translation.…”

“…131 Stimuli that induce LTP also persistently activate CaMKII, which may be critical for the molecular memory of synaptic events. 132 There is evidence that CaMKII is regulated by Fmrp, since wild-type mice, but not Fmr1-null mice, demonstrate activity-dependent increases in levels of hippocampal aCaMKII, the a-subunit of CaMKII, following mGluR-LTD. 103 Induction of aCaM-KII protein synthesis following N-methyl-d-aspartate (NMDA)/glutamate stimulation is also absent in synaptoneurosome preparations from FXS-model mice, in comparison to wild-type controls. 133 The dysregulation of CaMKII translation could have direct effects on the maintenance of synaptic memory, and might also alter function in other genes relevant to human disorders with autism symptomatology.…”

Magnesium in the Central Nervous System

“…Results demonstrated that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for Fragile X and related developmental disorders. In line with this observation, Hou et al, (2006) demonstrated that mGluR--LTD induces a transient, translation--dependent increase in FMRP that is rapidly degraded by the ubiquitin--proteasome pathway.…”