Postsynaptic p47phox regulates long-term depression in the hippocampus

Jee Hyun Yi,Philip Regan,Thomas M Piers,Kwangwook Cho,Seung Chan Kim,Daniel J Whitcomb,Dong Hyun Kim

doi:10.1038/s41421-018-0046-x

Jee Hyun Yi, Philip Regan + Show 5 more

Open Access

https://doi.org/10.1038/s41421-018-0046-x

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Abstract

It is well documented that reactive oxygen species (ROS) affects neurodegeneration in the brain. Several studies also implicate ROS in the regulation of synapse function and learning and memory processes, although the precise source of ROS generation within these contexts remains to be further explored. Here we show that postsynaptic superoxide generation through PKCζ-activated NADPH oxidase 2 (NOX2) is critical for long-term depression (LTD) of synaptic transmission in the CA1–Shaffer collateral synapse of the rat hippocampus. Specifically, PKCζ-dependent phosphorylation of p47phox at serine 316, a NOX2 regulatory subunit, is required for LTD but is not necessary for long-term potentiation (LTP). Our data suggest that postsynaptic p47phox phosphorylation at serine 316 is a key upstream determinant for LTD and synapse weakening.

Highlights

Synapse weakening is part of a group of physiological processes referred to as synaptic plasticity, which govern changes in synaptic function in response to neuronal activity, and are thought to represent the cellular and molecular mechanisms of learning and memory[1]
Superoxide ions are one of the primary forms of reactive oxygen species (ROS) and are known to be elevated in neurons following the activation of N-methyl-D-aspartate receptors (NMDARs)[14,15,16]
We hypothesized that intra-neuronal superoxide radicals are upstream regulators of NMDAR-dependent forms of synaptic plasticity

Summary

Introduction

Synapse weakening is part of a group of physiological processes referred to as synaptic plasticity, which govern changes in synaptic function in response to neuronal activity, and are thought to represent the cellular and molecular mechanisms of learning and memory[1]. Mounting evidence suggests that apoptotic signalling cascades, including caspase-3 and glycogen synthase kinase 3β (GSK-3β) activation, are centrally involved in physiological and pathophysiological forms of synapse weakening, manifest through postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis and long-term depression (LTD) of synaptic transmission[4,5,6]. How these signals are first initiated is unknown. To date there has been no characterization or elucidation of the precise mechanisms of ROS generation that regulate synaptic plasticity

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