E. Aloisi, A. Frick et al. in Nature Communication
Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice.
Le 21 novembre 2017
Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Aloisi E, Le Corf K, Dupuis J, Zhang P, Ginger M, Labrousse V, Spatuzza M, Georg Haberl M, Costa L, Shigemoto R, Tappe-Theodor A, Drago F, Vincenzo Piazza P, Mulle C, Groc L, Ciranna L, Catania MV, Frick A. Nat Commun. 2017 Oct 24;8(1):1103. doi: 10.1038/s41467-017-01191-2.
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and a frequent cause of autism spectrum disorder (ASD). Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of FXS. However, its dysfunction at the sub-cellular level ⎯ in relation to the synaptic and cognitive phenotypes in FXS ⎯ is largely unexplored. mGluR5 associates with a number of synaptic proteins and these interactions strongly influence the dynamic properties of the receptor at the synapse, as well as the function of other membrane receptors. Previous work has demonstrated that the interaction between mGluR5 and long forms of the scaffolding protein, Homer, is reduced in Fmr1 knockout mice (the mouse model for FXS) and that these alterations are caused by an overexpression of the short, activity-regulated Homer isoform, Homer 1a. The consequences of this altered interaction for receptor dynamics had not, however, been previously investigated.
In this study, we probed the consequences of the aforementioned mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that individual mGluR5 was significantly more mobile at synapses in hippocampal Fmr1KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-term depression, and NMDAR/hippocampus dependent cognitive deficits. Crucially, these synaptic and behavioral phenomena were reversed by knocking down the short, activity-related Homer1a in the hippocampus of Fmr1 KO mice.
Our study provides an important mechanistic link between changes in mGluR5 dynamics at synaptic sites and pathological phenotypes of FXS. These findings are likely to have important consequences for the future development of therapeutic agents/strategies for the treatment of FXS. In particular, both mGluR5 and NMDAR have been proposed as targets for therapeutic intervention in FXS and this altered crosstalk between these two receptors should be taken into consideration when predicting the outcome of single or combined therapies. In addition, correcting the altered balance between GluR5/Homer and mGluR5/NMDAR might provide a promising alternative for the development of novel therapeutic agents for the treatment of FXS and ASD.
Model for dysfunction of the NMDAR/mGluR5 crosstalk in Fmr1 KO neurons and its functional consequences. In WT neurons, a co-clustering of mGluR5 and NMDAR is prevented. In Fmr1 KO neurons, mGluR5 is disengaged from the long Homer protein–containing complex and more associated with the short Homer isoform, Homer1a, increasing the lateral diffusion of mGluR5 and promoting its interaction with synaptic NMDAR. This configuration causes defects in the function and plasticity of NMDAR, as well as deficits in cognitive tasks (here novel object recognition) (Fmr1 KO AAV-scr). Knockdown of Homer 1a (Fmr1 KO AAV-sh H1a) rescues these synaptic and cognitive defects.