title: Fmr1 KO and fenobam treatment differentially impact distinct synapse populations of mouse neocortex.
abstract: 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.
authors.affiliation: Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA. Electronic address: drwonder@gmail.com.
authors.forename: Gordon X
authors.initials: GX
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Allen Institute for Brain Science, Seattle, WA 98103, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smith
authors.affiliation: Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; INSERM 1024, Ecole Normale Supérieure Paris, 75005, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Mourrain
mesh_terms: D000818:Animals; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C512309:FXR2 protein, mouse; C497684:Fmr1 protein, mouse; C496283:Fxr1h protein, mouse; C032794:fenobam