Fmr1 KO and Fenobam Treatment Differentially Impact Distinct Synapse Populations of Mouse Neocortex

• Published in: Neuron (Cambridge, Mass.) Vol. 84; no. 6; pp. 1273 - 1286
• Main Authors: Wang, Gordon X., Smith, Stephen J, Mourrain, Philippe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.12.2014
• Subjects: Animals; Fragile X Mental Retardation Protein - genetics; Fragile X Syndrome - drug therapy; Fragile X Syndrome - metabolism; Imidazoles - pharmacology; Male; Mice; Mice, Knockout; Neocortex - cytology; Neocortex - drug effects; Neocortex - metabolism; Nerve Tissue Proteins - metabolism; RNA-Binding Proteins - metabolism; Synapses - drug effects; Synapses - metabolism
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2014.11.016

Cognitive deficits in fragile X syndrome (FXS) are attributed to molecular abnormalities of the brain’s vast and heterogeneous synapse populations. Unfortunately, the density of synapses coupled with their molecular heterogeneity presents formidable challenges in understanding the specific contribution of synapse changes in FXS. We demonstrate powerful new methods for the large-scale molecular analysis of individual synapses that allow quantification of numerous specific changes in synapse populations present in the cortex of a mouse model of FXS. Analysis of nearly a million individual synapses reveals distinct, quantitative changes in synaptic proteins distributed across over 6,000 pairwise metrics. Some, but not all, of these synaptic alterations are reversed by treatment with the candidate therapeutic fenobam, an mGluR5 antagonist. These patterns of widespread, but diverse synaptic protein changes in response to global perturbation suggest that FXS and its treatment must be understood as a networked system at the synapse level. •Single-synapse analysis reveals synapse- and circuit-specific phenotypes in FXS•Synaptic and total cellular protein levels are differentially perturbed by FMRP loss•Molecular features of synapse populations are diagnostic of FXS neural networks•Fenobam rescue of protein perturbations in Fmr1 KO is synapse class specific Wang et al. analyze the molecular composition of over a million individual synapses in a mouse model of FXS and reveal differential and heterogeneous effects across all scales, from molecules to synapses to cell assemblies.