Disrupted mGluR5-Homer scaffolds mediate abnormal mGluR5 signaling, circuit function and behavior in a mouse model of Fragile X Syndrome

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nature Neuroscience (Impact Factor: 16.1). 01/2012; 15(3):431-40, S1. DOI: 10.1038/nn.3033
Source: PubMed


Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of fragile X syndrome, a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the fragile X syndrome mouse model, Fmr1 knockout (Fmr1(-/y)). In Fmr1(-/y) mice, mGluR5 was less associated with long Homer isoforms but more associated with the short Homer1a. Genetic deletion of Homer1a restored mGluR5-long Homer scaffolds and corrected several phenotypes in Fmr1(-/y) mice, including altered mGluR5 signaling, neocortical circuit dysfunction and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wild-type mice mimicked many Fmr1(-/y) phenotypes. In contrast, Homer1a deletion did not rescue altered mGluR-dependent long-term synaptic depression or translational control of target mRNAs of fragile X mental retardation protein, the gene product of Fmr1. Our findings reveal new functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.

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    • "Although much work has focused on dysregulation of mGlu5 signaling to synaptic protein synthesis, emerging evidence finds abnormal mGlu5 receptor interactions with its scaffolding Homer protein, which results in mGlu5 receptor dysfunction and phenotypes independent of signaling to protein synthesis (D'Antoni et al., 2014). In particular, in the brain of Fmr1 knock-out mice, mGlu5 receptors are less associated to the constitutive forms of Homer proteins (Giuffrida et al., 2005; Ronesi et al., 2012). In the absence of FMRP, several properties and functions of mGlu5 receptors are altered, partly as a consequence of mGlu5/Homer disruption. "
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    • "One response is mediated by a synaptic plasticity process known as long term depression (LTD; Huber et al., 2002; Bear et al., 2004). Additional studies also reveal that pharmacological intervention of mGluR activation can rescue the FXS phenotype in the Fmr1 mouse model suggesting a therapeutic role for inhibitors of mGluR activity- specifically type 1 and type 5 receptor activity (Dölen et al., 2007; Michalon et al., 2012; Ronesi et al., 2012). Due to initial early success of 2-methyl-6-(phenylethynyl)pyridine (MPEP), fenobam and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), the use of mGluR5 antagonists remains a primary treatment option for FXS (Porter et al., 2005; Yan et al., 2005; Lindemann et al., 2011). "
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    • "Although Homers are known to be associated with UPS [40], thus far, Homer1a is the only isoform that has been confirmed as being ubiquitinated [40] [41] [42]. Homer1a, a short splice variant of Homer1, lacks a coiled-coil domain for oligomerization [43] and has been suggested to be a competitor of full-length Homers in multiple signaling pathways [43] [44]. The ubiquitination of Homer1a occurs at an 11-amino acid region in its C-terminal end [42] and is thought to play a role in synapse plasticity [45]. "
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