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Neuron. 2014 Dec 17;84(6):1273-86. doi: 10.1016/j.neuron.2014.11.016.

Fmr1 KO and fenobam treatment differentially impact distinct synapse populations of mouse neocortex.

Author information

1
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.
2
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Allen Institute for Brain Science, Seattle, WA 98103, USA.
3
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.

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.

PMID:
25521380
PMCID:
PMC4479348
DOI:
10.1016/j.neuron.2014.11.016
[Indexed for MEDLINE]
Free PMC Article

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