Journal Article

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

Chen, Yaomin, Zhang, Yun-wu, Cai, Lei, Gage, Fred H, Wang, Xin, Wu, Chengbiao, Zhang, Dongxian, Mu, Yangling, Zhou, Ying, Hong, Wanjin, Lipton, Stuart A, Thompson, Robert C, Zhang, Xiaofei, Zhao, Yingjun, Bu, Guojun, Ranscht, Barbara, Johnson, Peter F, Badie, Hedieh, Yang, Bo, Loo, Li Shen, Mobley, William C, Xu, Huaxi

2013

Overview

Synaptic abnormalities and learning dysfunction are prominent characteristics of Down's syndrome. Now Huaxi Xu and colleagues show that expression of the protein SNX27 is reduced in Down's syndrome brains and that restoring its expression can ameliorate learning dysfunction in a mouse model of the disease. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/80/86 / 692/699/375 / Analysis / Animals / Antineoplastic Combined Chemotherapy Protocols / Biomedicine / Brain research / C-Reactive Protein - physiology / Cancer Research / CCAAT-Enhancer-Binding Protein-beta / CCAAT-Enhancer-Binding Proteins - physiology / Cerebral Cortex - cytology / Cerebral Cortex - physiopathology / Cisplatin / Down syndrome / Down Syndrome - physiopathology / Down-Regulation / Female / Gene expression / Genetic aspects / Hippocampus - cytology / Hippocampus - physiopathology / Humans / Ifosfamide / Infectious Diseases / Male / Metabolic Diseases / Mice / Mice, Inbred C57BL / Mice, Knockout / MicroRNAs - physiology / Mitomycin / Molecular biology / Molecular Medicine / Nerve Tissue Proteins - physiology / Neurology / Neurosciences / Neurotransmitters / Pathology / Proteins / Receptors, Glutamate - metabolism / Recycling / Sorting Nexins - physiology / Synapses / Synapses - physiology / Transcription Factors - physiology