Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome

Abstract

Enhanced mGluR5 function is causally associated with the pathophysiology of Fragile X Syndrome (FXS), 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 FXS mouse model, Fmr1 KO. In Fmr1 KO mice mGluR5 is less associated with long Homer isoforms, but more associated with the short Homer1a. Genetic deletion of Homer1a restores mGluR5- long Homer scaffolds and corrects multiple phenotypes in Fmr1 KO mice including altered mGluR5 signaling, neocortical circuit dysfunction, and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wildtype mice mimics many Fmr1 KO phenotypes. In contrast, Homer1a deletion does not rescue altered mGluR-dependent long-term synaptic depression or translational control of FMRP target mRNAs. Our findings reveal novel functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism.

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

“…2B). Such lower interaction is also observed in FMR1 knockout and is proposed to lead to constitutive activation of mGlu5 (Ronesi et al, 2012). We also found that the mGlu5-Homer interaction was reduced in wildtype animals after DHPG treatment (P , 0.05, unpaired t test).…”

“…Homer proteins are known to link mGluRs to other postsynaptic density proteins (Shiraishi-Yamaguchi and Furuichi, 2007;Niswender and Conn, 2010) and play a vital role in coupling the receptors with downstream effectors (Mao et al, 2005;Jung et al, 2007;Won et al, 2009). Disrupted interaction between mGlu5 and the long isoform of Homer leads to deficits in mTOR signaling, protein translation, as well as synaptic plasticity in the FMR1 knockout mouse model (Ronesi and Huber, 2008;Ronesi et al, 2012). We found that the Akt-mTOR phosphorylation was increased under basal conditions in the GluD1 KO.…”

“…In light of the potential interaction between GluD1 and mGlu5, it is conceivable that loss of GluD1 may affect the scaffolding interactions of mGlu5 if GluD1 serves as a mediator of these interactions or helps stabilize these interactions. It is well known that mGlu5 interacts with long isoforms of Homer (Homer 1b, 1c, 2, and 3), and the mGlu5-Homer interaction is critical for downstream mTOR signaling (Kato et al, 1998;Tu et al, 1999;Ronesi and Huber, 2008;Ronesi et al, 2012). Using immunoprecipitation and western blotting, we assessed whether loss of GluD1 affects the mGlu5-Homer coupling.…”

“…The mGlu5-Homer interaction is known to regulate the downstream mTOR signaling (Ronesi et al, 2012). Activation of mTOR complexes, mTORC1 and mTORC2, downstream of mGlu5 activation leads to protein translation and actin reorganization, respectively, and is critical for functional and structural plasticity.…”

Shank mutant mice as an animal model of autism

“…Most notably, FMRP knock-out (KO) mice have increased levels of protein synthesis and show enhanced mGluR-dependent long-term depression (mGluR-LTD) in the hippocampus [27] as well as impaired long-term potentiation (LTP) in the amygdala [28,29]. It has been shown that the synaptic-level symptoms in these mice are caused by increased sensitivity to mGluR5 signalling and extracellular signal-regulated kinase (ERK)-1/2 [30], and that this is related to a disrupted balance of Homer isoforms [31]. In addition to this, TSC1, a negative regulator of mammalian target of rapamycin (mTOR), which is upstream of FMRP, has been implicated in autistic symptoms through tuberous sclerosis (TSC) [32][33][34], and also tested in a mouse model [18].…”