@article{3622063e550a463a9b04fe578e2d607f,
title = "Synaptic adhesion molecule Pcdh-γC5 mediates synaptic dysfunction in Alzheimer{\textquoteright}s disease",
abstract = "Synaptic dysfunction and neuronal excitatory/inhibitory imbalance have been implicated in Alzheimer{\textquoteright}s disease (AD) pathogenesis. Although intensive studies have been focused on the excitatory synaptic system, much less is known concerning the mechanisms mediating inhibitory synaptic dysfunction in AD. We reported previously that protocadherin-κC5 (Pcdh-κC5), a member of clustered Pcdh-κ subfamily of cadherin-type synaptic adhesion proteins, functions to promote GABAergic synaptic transmission. We reveal here that Pcdh-κC5 is enriched in vesicular GABA transporter-positive synaptic puncta and its expression levels are increased in neuronal hyperexcitation conditions, upon β-amyloid (Aβ) treatment, and in amyloid precursor protein (APP)/presenilin-1 (PS1)-transgenic mice of both sexes. This is associated with elevated levels of GABAergic proteins and enhanced synaptic inhibition. Genetic knock-down experimentsshowedthatPcdh-κC5modulatesspontaneoussynapticcurrentsandAβ-inducedsynapticalterationsdirectly. Ourresultssupport a model in which Pcdh-κC5 senses neuronal hyperexcitation to augment GABAergic inhibition. This adaptive mechanism may be dysregulated under chronic excitation conditions such as AD, leading to aberrant Pcdh-κC5 expression and associated synaptic dysfunction.",
keywords = "Alzheimer{\textquoteright}s disease, GABA, Mice, Pcdh-κC5, Synaptic transmission",
author = "Yanfang Li and Zhicai Chen and Yue Gao and Gaojie Pan and Honghua Zheng and Yunwu Zhang and Huaxi Xu and Guojun Bu and Hui Zheng",
note = "Funding Information: Received April 18, 2017; revised July 22, 2017; accepted Aug. 14, 2017. Author contributions: Y.L. and Hui Zheng designed research; Y.L., Z.C., Y.G., and G.P. performed research; Hon-ghua Zheng, Y.-Z., H.X., G.B., and Hui Zheng contributed unpublished reagents/analytic tools; Y.L., Z.C., Y.G., G.P., and Hui Zheng analyzed data; Y.L. and Hui Zheng wrote the paper. ThisworkwassupportedbyNaturalScienceFoundationofFujianProvinceofChina(Grant2017J01151and2016J01411),the National Natural Science Foundation of China (Grant 81301105 and 81771164), National Institutes of Health (Grant R01 AG032051),andtheNationalKeyResearchandDevelopmentProgramofChina(Grant2016YFC1305903). The authors declare no competing financial interests. Correspondence should be addressed to either Yanfang Li or Hui Zheng, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361005 Fujian, China. E-mail: yfli@xmu.edu.cn or huiz@bcm.edu. DOI:10.1523/JNEUROSCI.1051-17.2017 Copyright {\textcopyright} 2017 the authors 0270-6474/17/379259-10$15.00/0 Publisher Copyright: {\textcopyright} 2017 the authors.",
year = "2017",
month = sep,
day = "20",
doi = "10.1523/JNEUROSCI.1051-17.2017",
language = "English (US)",
volume = "37",
pages = "9259--9268",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "38",
}