title: 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.
authors.affiliation: Center for Neuroscience, Aging and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Hedieh
authors.initials: H
authors.lastname: Badie
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yangling
authors.initials: Y
authors.lastname: Mu
authors.forename: Li Shen
authors.initials: LS
authors.lastname: Loo
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.forename: Robert C
authors.initials: RC
authors.lastname: Thompson
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Yaomin
authors.initials: Y
authors.lastname: Chen
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Barbara
authors.initials: B
authors.lastname: Ranscht
authors.forename: Yun-wu
authors.initials: YW
authors.lastname: Zhang
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D002097:C-Reactive Protein / Q000502:physiology; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000503:physiopathology; D002945:Cisplatin; D004314:Down Syndrome / Q000503:physiopathology*; D015536:Down-Regulation; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000503:physiopathology; D006801:Humans; D007069:Ifosfamide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology; D016685:Mitomycin; D009419:Nerve Tissue Proteins / Q000502:physiology; D017470:Receptors, Glutamate / Q000378:metabolism*; D058305:Sorting Nexins / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; D002945:Cisplatin; D007069:Ifosfamide; D035683:MicroRNAs; D016685:Mitomycin; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; D058305:Sorting Nexins; D014157:Transcription Factors; D000099153:Pentraxins; C545012:CEBPB protein, human; C524942:MIRN155 microRNA, human; C500393:Snx27 protein, mouse