title: APP modulates KCC2 expression and function in hippocampal GABAergic inhibition.
abstract: Amyloid precursor protein (APP) is enriched at the synapse, but its synaptic function is still poorly understood. We previously showed that GABAergic short-term plasticity is impaired inAppknock-out (App-/-) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission has remained elusive. Using electrophysiological, biochemical, moleculobiological, and pharmacological analysis, here we show that APP can physically interact with KCC2, a neuron-specific K+-Cl-cotransporter that is essential for Cl-homeostasis and fast GABAergic inhibition. APP deficiency results in significant reductions in both total and membrane KCC2 levels, leading to a depolarizing shift in the GABA reversal potential (EGABA). Simultaneous measurement of presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) in hippocampal neurons reveals impaired unitary IPSC amplitudes attributable to a reduction in α1 subunit levels of GABAAR. Importantly, restoration of normal KCC2 expression and function inApp-/-mice rescues EGABA, GABAAR α1 levels and GABAAR mediated phasic inhibition. We show that APP functions to limit tyrosine-phosphorylation and ubiquitination and thus subsequent degradation of KCC2, providing a mechanism by which APP influences KCC2 abundance. Together, these experiments elucidate a novel molecular pathway in which APP regulates, via protein-protein interaction with KCC2, GABAAR mediated inhibition in the hippocampus.
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Jinzhao
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Psychology and Center for Studies of Psychological Application, South China Normal University, Guangzhou, China.|Brain Science Institute, South China Normal University, Guangzhou, China.
authors.forename: Jinxiang
authors.initials: J
authors.lastname: Jiang
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Justice
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Ran
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Huo
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, United States.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Lu
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: School of Life Sciences, South China Normal University, Guangzhou, China.|Brain Science Institute, South China Normal University, Guangzhou, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Long
authors.affiliation: School of Psychology and Center for Studies of Psychological Application, South China Normal University, Guangzhou, China.|Brain Science Institute, South China Normal University, Guangzhou, China.|Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, China.
authors.forename: Li
authors.identifier: 0000-0001-7448-8588
authors.initials: L
authors.lastname: Yang
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D059330:GABAergic Neurons / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D027981:Symporters / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D016564:Amyloid beta-Protein Precursor; D027981:Symporters; C545487:APP protein, human; C000606816:SLC12A5 protein, human; D000096922:K Cl- Cotransporters
keywords: APP; GABA reversal potential; IPSC; KCC2; hippocampus; mouse; neuroscience; protein-protein interaction