APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

作者：Chen, Ming; Wang, Jinzhao; Jiang, Jinxiang; Zheng, Xingzhi; Justice, Nicholas J.; Wang, Kun; Ran, Xiangqian; Li, Yi; Huo, Qingwei; Zhang, Jiajia; Li, Hongmei; Lu, Nannan; Wang, Ying; Zheng, Hui; Long, Cheng; Yang, Li^*

来源：eLife, 2017, 6: e20142.

DOI：10.7554/eLife.20142

• AMYLOID PRECURSOR PROTEIN
• CATION-CHLORIDE COTRANSPORTERS
• ALZHEIMERS-DISEASE
• SYNAPTIC PLASTICITY
• GABA(A) RECEPTOR
• DOWN-REGULATION
• MOUSE MODEL
• BETA
• SYNAPSES
• DISORDERS

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 a1 subunit levels of GABAAR. Importantly, restoration of normal KCC2 expression and function in App(-/-) mice rescues E-GABA, GABA(A)R alpha 1 levels and GABA(A)R 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, GABA(A)R mediated inhibition in the hippocampus.

• 出版日期2017-1-5