Abstract
BackgroundAutism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors. Mouse models of specific risk factors have been successful in identifying molecular mechanisms associated with a given factor. However, comparisons among different models to elucidate underlying common pathways or to define clusters of biologically relevant disease subtypes have been complicated by different methodological approaches or different brain regions examined by the labs that developed each model. Here, we use a novel proteomic technique, quantitative multiplex co-immunoprecipitation or QMI, to make a series of identical measurements of a synaptic protein interaction network in seven different animal models. We aim to identify molecular disruptions that are common to multiple models.MethodsQMI was performed on 92 hippocampal and cortical samples taken from seven mouse models of ASD: Shank3B, Shank3Δex4-9, Ube3a2xTG, TSC2, FMR1, and CNTNAP2 mutants, as well as E12.5 VPA (maternal valproic acid injection on day 12.5 post-conception). The QMI panel targeted a network of 16 interacting, ASD-linked, synaptic proteins, probing 240 potential co-associations. A custom non-parametric statistical test was used to call significant differences between ASD models and littermate controls, and Hierarchical Clustering by Principal Components was used to cluster the models using mean log2 fold change values.ResultsEach model displayed a unique set of disrupted interactions, but some interactions were disrupted in multiple models. These tended to be interactions that are known to change with synaptic activity. Clustering revealed potential relationships among models and suggested deficits in AKT signaling in Ube3a2xTG mice, which were confirmed by phospho-western blots.ConclusionsThese data highlight the great heterogeneity among models, but suggest that high-dimensional measures of a synaptic protein network may allow differentiation of subtypes of ASD with shared molecular pathology.
Highlights
Autism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors
In conclusion, we performed a series of identical Quantitative multiplex co-immunoprecipitation (QMI) experiments to measure differences in the abundance of, and binary interactions among, 16 synaptic proteins in 7 mouse models of autism
Many of the disrupted interactions were identified as activity-dependent interactions in a separate study, highlighting the complex relationships between ASD risk genes and activity-dependent homeostatic processes [21]
Summary
Autism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors. The fact that ASD is a diagnostic entity, with a common set of behavioral impairments shared among patients, has led to the widespread hypothesis that other disease mechanisms must be shared among patients at the level of anatomy [10], neural circuits [11], genetic networks [12, 13], or molecular pathways [14] Along these lines, a few clear themes have emerged from combining diverse lines of evidence: the immune system is likely involved, with immune-mediated risk factors (reviewed in [15]), and abnormal peripheral [16] and central ([17, 18], but see [19]) inflammatory phenotypes present. Diverse ASD-linked genes can disrupt the complex molecular circuitry that translates synaptic ion currents into intracellular signal transduction cascades, traffics those messages to sites of translation and transcription, and converts protein-level modifications into long-term changes in gene expression
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