APP modulates KCC2 expression and function in hippocampal GABAergic inhibition
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 in App knock-out (App-/-) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/20142 |
| _version_ | 1818018575816851456 |
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| author | Ming Chen Jinzhao Wang Jinxiang Jiang Xingzhi Zheng Nicholas J Justice Kun Wang Xiangqian Ran Yi Li Qingwei Huo Jiajia Zhang Hongmei Li Nannan Lu Ying Wang Hui Zheng Cheng Long Li Yang |
| author_facet | Ming Chen Jinzhao Wang Jinxiang Jiang Xingzhi Zheng Nicholas J Justice Kun Wang Xiangqian Ran Yi Li Qingwei Huo Jiajia Zhang Hongmei Li Nannan Lu Ying Wang Hui Zheng Cheng Long Li Yang |
| author_sort | Ming Chen |
| collection | DOAJ |
| description | 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 in App knock-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 in App-/- 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. |
| first_indexed | 2024-04-14T07:41:29Z |
| format | Article |
| id | doaj.art-8e207d25bc614b78bbfd86a5fa0637ac |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:41:29Z |
| publishDate | 2017-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8e207d25bc614b78bbfd86a5fa0637ac2022-12-22T02:05:29ZengeLife Sciences Publications LtdeLife2050-084X2017-01-01610.7554/eLife.20142APP modulates KCC2 expression and function in hippocampal GABAergic inhibitionMing Chen0Jinzhao Wang1Jinxiang Jiang2Xingzhi Zheng3Nicholas J Justice4Kun Wang5Xiangqian Ran6Yi Li7Qingwei Huo8Jiajia Zhang9Hongmei Li10Nannan Lu11Ying Wang12Hui Zheng13Cheng Long14Li Yang15https://orcid.org/0000-0001-7448-8588School of Life Sciences, South China Normal University, Guangzhou, ChinaSchool of Life Sciences, South China Normal University, Guangzhou, ChinaSchool of Psychology and Center for Studies of Psychological Application, South China Normal University, Guangzhou, China; Brain Science Institute, South China Normal University, Guangzhou, ChinaSchool of Life Sciences, South China Normal University, Guangzhou, ChinaInstitute of Molecular Medicine, University of Texas Health Sciences Center, Houston, United StatesSchool of Life Sciences, South China Normal University, Guangzhou, ChinaSchool of Life Sciences, South China Normal University, Guangzhou, ChinaSchool of Life Sciences, South China Normal University, Guangzhou, ChinaSchool of Life Sciences, South China Normal University, Guangzhou, ChinaSchool of Life Sciences, South China Normal University, Guangzhou, ChinaHuffington Center on Aging, Baylor College of Medicine, Houston, United StatesSchool of Life Sciences, South China Normal University, Guangzhou, ChinaSchool of Life Sciences, South China Normal University, Guangzhou, ChinaHuffington Center on Aging, Baylor College of Medicine, Houston, United StatesSchool of Life Sciences, South China Normal University, Guangzhou, China; Brain Science Institute, South China Normal University, Guangzhou, ChinaSchool 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, ChinaAmyloid 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 in App knock-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 in App-/- 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.https://elifesciences.org/articles/20142APPKCC2hippocampusGABA reversal potentialIPSCprotein-protein interaction |
| spellingShingle | Ming Chen Jinzhao Wang Jinxiang Jiang Xingzhi Zheng Nicholas J Justice Kun Wang Xiangqian Ran Yi Li Qingwei Huo Jiajia Zhang Hongmei Li Nannan Lu Ying Wang Hui Zheng Cheng Long Li Yang APP modulates KCC2 expression and function in hippocampal GABAergic inhibition eLife APP KCC2 hippocampus GABA reversal potential IPSC protein-protein interaction |
| title | APP modulates KCC2 expression and function in hippocampal GABAergic inhibition |
| title_full | APP modulates KCC2 expression and function in hippocampal GABAergic inhibition |
| title_fullStr | APP modulates KCC2 expression and function in hippocampal GABAergic inhibition |
| title_full_unstemmed | APP modulates KCC2 expression and function in hippocampal GABAergic inhibition |
| title_short | APP modulates KCC2 expression and function in hippocampal GABAergic inhibition |
| title_sort | app modulates kcc2 expression and function in hippocampal gabaergic inhibition |
| topic | APP KCC2 hippocampus GABA reversal potential IPSC protein-protein interaction |
| url | https://elifesciences.org/articles/20142 |
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