Article

Synaptopathies: diseases of the synaptome

Genes to Cognition Programme, Centre for Clinical Brain Sciences, The University of Edinburgh, Chancellors Building, 47 Little France Crescent, Edinburgh EH16 4SB, United Kingdom.
Current opinion in neurobiology (Impact Factor: 6.63). 03/2012; 22(3):522-9. DOI: 10.1016/j.conb.2012.02.002
Source: PubMed

ABSTRACT

The human synapse proteome is a highly complex collection of proteins that is disrupted by hundreds of gene mutations causing over 100 brain diseases. These synaptic diseases, or synaptopathies, cause major psychiatric, neurological and childhood developmental disorders through mendelian and complex genetic mechanisms. The human postsynaptic proteome and its core signaling complexes built by the assembly of receptors and enzymes around Membrane Associated Guanylate Kinase (MAGUK) scaffold proteins are a paradigm for systematic analysis of synaptic diseases. In humans, the MAGUK Associated Signaling Complexes are mutated in Autism, Schizophrenia, Intellectual Disability and many other diseases, and mice carrying orthologous mutations show relevant cognitive, social, motoric and other phenotypes. Diseases with similar phenotypes and symptom spectrums arise from disruption of complexes and interacting proteins within the synapse proteome. Classifying synaptic disease phenotypes with genetic and proteome data provides a new brain disease classification system based on molecular etiology and pathogenesis.

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    • "Proper formation and function of synapses require the coordinated assembly of large and heterogeneous protein complexes on the pre-and postsynaptic side. The composition of the synaptic proteome varies with synaptic neurotransmitter type and developmental stage, changes upon activity-induced changes in synaptic strength, and is affected in synaptopathies (Cajigas et al., 2010; Grant, 2012). "
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    ABSTRACT: The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Neuron
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    • "Similarly, synaptic alterations are found in mouse models of these disorders (Comery et al., 1997). Moreover, multiple genetic variations associated with neurodevelopmental disorders are found in genes that have defined roles in synaptic regulation (Grant, 2012; Peca and Feng, 2012). Despite the important role of impaired synaptic development in ASD, in vivo analyses of synapse formation and function in MIA offspring are limited (Ito et al., 2010; Elmer et al., 2013). "
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    ABSTRACT: Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment. Copyright © 2015. Published by Elsevier Inc.
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    • "Cognitive deficits in neurological diseases are often attributed to synapse abnormalities (Bhakar et al., 2012; Coghlan et al., 2012; Garden and La Spada, 2012; Grant, 2012; Sheng et al., 2012). The understanding of these abnormalities is complicated by the heterogeneity of the brain's vast synapse populations (Bayé s et al., 2011; Emes and Grant, 2012; O'Rourke et al., 2012). "
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    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. Copyright © 2014 Elsevier Inc. All rights reserved.
    No preview · Article · Dec 2014 · Neuron
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