Synaptopathies: diseases of the synaptome
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.
- SourceAvailable from: Jeffrey N Savas
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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). "
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.Neuron 08/2015; 87(4):764-80. DOI:10.1016/j.neuron.2015.08.007 · 15.05 Impact Factor
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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). "
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.Brain Behavior and Immunity 07/2015; DOI:10.1016/j.bbi.2015.07.022 · 5.89 Impact Factor
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- "DLGAP2 (also known as SAPAP2 or GKAP2), as one of the main components of postsynaptic scaffolding proteins, directly interacts with DLG4 (also known as PSD-95) and SHANKs to form the DLG4-DLGAPs-SHANKs complex, which plays critical roles in synaptic morphogenesis and functions [12-14]. Human genetic studies point out that mutations of synaptic scaffold proteins may contribute to the etiology of psychiatric and neurodevelopmental disorders [15,16]. Further, DLG4, SHANKs[18-20] and DLGAP2[8,21,22] have been listed as possible candidate genes for autism. "
ABSTRACT: Background: As elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Recently, many studies have pointed out that synaptic protein-associated mutations may lead to dysfunctions of social cognition. Dlgap2, which encodes one of the main components of scaffold proteins in postsynaptic density (PSD), has been addressed as a candidate gene in autism spectrum disorders. To elucidate the disturbance of synaptic balance arising from Dlgap2 loss-of-function in vivo, we thus generated Dlgap2 (-/-) mice to investigate their phenotypes of synaptic function and social behaviors. Methods: The creation of Dlgap2 (-/-) mice was facilitated by the recombineering-based method, Cre-loxP system and serial backcross. Reversal learning in a water T-maze was used to determine repetitive behaviors. The three-chamber approach task, resident-intruder test and tube task were performed to characterize the social behaviors of mutant mice. Cortical synaptosomal fraction, Golgi-Cox staining, whole-cell patch electrophysiology and transmission electron microscopy were all applied to investigate the function and structure of synapses in the orbitofrontal cortex (OFC) of Dlgap2 (-/-) mice. Results: Dlgap2 (-/-) mice displayed exacerbated aggressive behaviors in the resident-intruder task, and elevated social dominance in the tube test. In addition, Dlgap2 (-/-) mice exhibited a clear reduction of receptors and scaffold proteins in cortical synapses. Dlgap2 (-/-) mice also demonstrated lower spine density, decreased peak amplitude of miniature excitatory postsynaptic current and ultra-structural deficits of PSD in the OFC. Conclusions: Our findings clearly demonstrate that Dlgap2 plays a vital role in social behaviors and proper synaptic functions of the OFC. Moreover, these results may provide valuable insights into the neuropathology of autism.Molecular Autism 05/2014; 5(1):32. DOI:10.1186/2040-2392-5-32 · 5.41 Impact Factor