APP modulates KCC2 expression and function in hippocampal GABAergic inhibition
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
Affiliations
Ming Chen
School of Life Sciences, South China Normal University, Guangzhou, China
Jinzhao Wang
School of Life Sciences, South China Normal University, Guangzhou, China
Jinxiang Jiang
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
Xingzhi Zheng
School of Life Sciences, South China Normal University, Guangzhou, China
Nicholas J Justice
Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, United States
Kun Wang
School of Life Sciences, South China Normal University, Guangzhou, China
Xiangqian Ran
School of Life Sciences, South China Normal University, Guangzhou, China
Yi Li
School of Life Sciences, South China Normal University, Guangzhou, China
Qingwei Huo
School of Life Sciences, South China Normal University, Guangzhou, China
Jiajia Zhang
School of Life Sciences, South China Normal University, Guangzhou, China
Hongmei Li
Huffington Center on Aging, Baylor College of Medicine, Houston, United States
Nannan Lu
School of Life Sciences, South China Normal University, Guangzhou, China
Ying Wang
School of Life Sciences, South China Normal University, Guangzhou, China
Hui Zheng
Huffington Center on Aging, Baylor College of Medicine, Houston, United States
Cheng Long
School of Life Sciences, South China Normal University, Guangzhou, China; Brain Science Institute, South China Normal University, Guangzhou, China
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
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.
