Abstract
Down syndrome (DS), the main genetic cause of intellectual disability, is associated with an imbalance of excitatory/inhibitory neurotransmitter systems. The phenotypic assessment and pharmacotherapy interventions in DS murine models strongly pointed out glutamatergic neurotransmission alterations (specially affecting ionotropic glutamate receptors [iGluRs]) that might contribute to DS pathophysiology, which is in agreement with DS condition. iGluRs play a critical role in fast-mediated excitatory transmission, a process underlying synaptic plasticity. Neuronal plasticity is biochemically modulated by post-translational modifications, allowing rapid and reversible adaptation of synaptic strength. Among these modifications, phosphorylation/dephosphorylation processes strongly dictate iGluR protein–protein interactions, cell surface trafficking, and subsynaptic mobility. Hence, we hypothesized that dysregulation of phosphorylation/dephosphorylation balance might affect neuronal function, which in turn could contribute to the glutamatergic neurotransmitter alterations observed in DS. To address this point, we biochemically purified subsynaptic hippocampal fractions from adult Ts65Dn mice, a trisomic mouse model recapitulating DS phenotypic alterations. Proteomic analysis showed significant alterations of the molecular composition of subsynaptic compartments of hippocampal trisomic neurons. Further, we characterized iGluR phosphopattern in the hippocampal glutamatergic synapse of trisomic mice. Phosphoenrichment-coupled mass spectrometry analysis revealed specific subsynaptic- and trisomy-associated iGluR phosphorylation signature, concomitant with differential subsynaptic kinase and phosphatase composition of Ts65Dn hippocampal subsynaptic compartments. Furthermore, biochemical data were used to build up a genotype-kinome-iGluR phosphopattern matrix in the different subsynaptic compartments. Overall, our results provide a precise profile of iGluR phosphopattern alterations in the glutamatergic synapse of the Ts65Dn mouse model and support their contribution to DS-associated synaptopathy. The alteration of iGluR phosphoresidues in Ts65Dn hippocampi, together with the kinase/phosphatase signature, identifies potential novel therapeutic targets for the treatment of glutamatergic dysfunctions in DS.
Highlights
Down syndrome (DS) is the most common genetic cause of intellectual disability (OMIM #190685)
The majority of kinases interacting with ionotropic glutamate receptor (iGluR) remarkably show an overall increase in trisomic samples, whereas the majority of iGluRrelated phosphatases show reduction, with some exceptions in both protein categories
These results are concomitant with the increased number of iGluR phosphopeptides identified by the phosphoproteomic analysis of Ts65Dn mice hippocampal postsynaptic fractions
Summary
Down syndrome (DS) is the most common genetic cause of intellectual disability (OMIM #190685). Ts65Dn treatment with memantine—a reversible N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist—has been shown to partially rescue critical electrophysiological alterations (Scott-McKean and Costa, 2011) and cognitive phenotypic abnormalities of trisomic mice (Costa et al, 2007; Lockrow et al, 2011).These findings have been significantly translated to the clinical practice, with an improvement of the cognitive skills of individuals with DS (Boada et al, 2012) These data strongly support the hypothesis that Hsa gene overexpression (e.g., DYRK1A, APP, TIAM1, and ITSN1 gene products) might dysregulate NMDAR expression and/or function, contributing to DS-like pathogenesis in trisomic mice (Siddiqui et al, 2008). Our results demonstrate an altered phosphopattern in the glutamatergic synapse, together with the identification of a protein kinase/phosphatase biochemical signature in the Ts65Dn murine model, which may represent novel therapeutic targets for DS synaptopathy
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