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Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome

Abstract

Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that Snx27−/− mice have severe neuronal deficits in the hippocampus and cortex. Although Snx27+/− mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein β (C/EBPβ) in Down's syndrome brains and identify C/EBPβ as a transcription factor for SNX27. Down's syndrome causes overexpression of miR-155, a chromosome 21–encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis.

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Figure 1: Neuropathology in the cortex and hippocampus of Snx27−/− mice.
Figure 2: Cognitive and synaptic deficits in Snx27+/− mice.
Figure 3: Downregulation of SNX27 affects the stability of NMDARs and AMPARs.
Figure 4: SNX27 interacts with glutamate receptors and regulates recycling to the cell surface.
Figure 5: Downregulation of C/EBPβ through overexpression of miR-155 results in decreased amounts of SNX27 in Down's syndrome brains.
Figure 6: SNX27 rescues cognitive and synaptic deficits in Ts65Dn mice.

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Acknowledgements

We thank P. Slesinger (Mount Sinai School of Medicine) for providing the rabbit SNX27-specific antibody and helpful discussion, A. Roberts and the Scripps behavioral core for mouse behavioral analysis, T. Golde and C. Ceballos (University of Florida) for generating AAV, E. Masliah (University of California, San Diego) for providing human brain specimens, P. Greengard (The Rockfeller University) for providing GluR1 and GluR2 constructs, K. Wright (University of California, San Diego) for helping in the transfer of Ts65Dn mice, S. Huang (Sanford-Burnham Medical Research Institute) for helping with statistical analysis, K. Saylor (US National Institutes of Health) for C/EBPβ knockout mouse breeding and tissue collection and A. Brzozowska-Prechtl and L. Lacarra for technical help. This work was supported in part by US National Institutes of Health grants (R01 AG038710, R01 AG021173, R01 NS046673, R01 AG030197 and R01 AG044420 to H.X.; and P01 HD29587, P01 ES016738, P30 NS076411 to S.A.L.) and grants from the Alzheimer's Association (to H.X. and Y. Zhang), the American Health Assistance Foundation (to H.X.), National Natural Science Foundation of China (30973150 and 81161120496 to Y. Zhang), the 973 Prophase Project (2010CB535004 to Y. Zhang) and Natural Science Funds for Distinguished Young Scholar of Fujian Province (2009J06022 to Y. Zhang). Y. Zhang is supported by the Program for New Century Excellent Talents in Universities (NCET), the Fundamental Research Funds for the Central Universities and Fok Ying Tung Education Foundation. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, US National Cancer Institute and Center for Cancer Research.

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Authors

Contributions

X.W. and H.X. conceptualized the study. X.W. designed and performed morphological analysis and biochemical assays, and Y. Zhao performed receptor endocytosis and recycling experiments. X.Z. performed mEPSC and LTP recordings in the SNX27 rescue experiments, and S.A.L. designed and helped analyze these experiments while supervising X.Z. H.B. and Y.M. performed extracellular electrophysiological recordings, and B.R. and F.H.G. supervised H.B. and Y.M., respectively. Y. Zhou analyzed miRNA expression in humans with Down's syndrome and the mouse model. L.S.L. performed endogenous coimmunoprecipitation assays. W.H. provided Snx27 knockout mice and SNX27-specific antibody and supervised L.S.L. and L.C. C.W. and W.C.M. provided Ts65Dn mice and discussion. R.C.T. performed mouse genotyping, Y.C. helped with collecting Alzheimer's disease samples, B.Y. and D.Z. performed whole-cell recordings, and P.F.J. provided C/EBPβ knockout mouse brain samples. Y. Zhang, G.B. and S.A.L. discussed and edited the manuscript. X.W. and H.X. wrote the manuscript. H.X. supervised the project.

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Correspondence to Huaxi Xu.

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Wang, X., Zhao, Y., Zhang, X. et al. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome. Nat Med 19, 473–480 (2013). https://doi.org/10.1038/nm.3117

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