APP modulates KCC2 expression and function in hippocampal GABAergic inhibition
- South China Normal University, China
- University of Texas Health Sciences Center, United States
- South China Normal University, United States
- Baylor College of Medicine, United States
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 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.
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Author details
Funding
National Natural Science Foundation of China (31171018,31171355)
- Cheng Long
- Li Yang
Natural Science Foundation of Guangdong Province (2014A030313418,2014A030313440)
- Cheng Long
- Li Yang
The Science and Technology Division of Guangdong Province (2013KJCX0054,201607010320)
- Li Yang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was conducted along the guidelines described in "The Guide for the Care and Use of Laboratory Animals" (Eighth Edition). All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#0312-11) of the South China Normal University. Every effort was made to minimize suffering.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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APP modulates KCC2 expression and function in hippocampal GABAergic inhibition
eLife 6:e20142.
https://doi.org/10.7554/eLife.20142
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Results:
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Conclusions:
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Funding:
The research is funded by Central University basic research young teachers and students research ability promotion sub-projec t(2023CDJYGRH-ZD06), and by Emergency Medicine Chongqing Key Laboratory Talent Innovation and development joint fund project (2024RCCX10).
