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Postsynaptic p47phox regulates long-term depression in the hippocampus.

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 PKC?-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, PKC?-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.

SUBMITTER: Yi JH

PROVIDER: S-EPMC6110736 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Postsynaptic p47phox regulates long-term depression in the hippocampus.

Yi Jee Hyun JH Kim Dong Hyun DH Piers Thomas M TM Piers Thomas M TM Kim Seung Chan SC Whitcomb Daniel J DJ Regan Philip P Cho Kwangwook K

Cell discovery 20180828

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 collatera ...[more]

PMID: 30181899

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Project description:Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requirements for induction of hippocampal spike timing-dependent long-term potentiation (t-LTP) and spike timing-dependent long-term depression (t-LTD) and the mechanisms of these 2 forms of plasticity at CA3-CA1 synapses in young (P12-P18) mouse hippocampus. We found that both t-LTP and t-LTD can be induced at hippocampal CA3-CA1 synapses by pairing presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz). Both t-LTP and t-LTD require NMDA-type glutamate receptors for their induction, but the location and properties of these receptors are different: While t-LTP requires postsynaptic ionotropic NMDA receptor function, t-LTD does not, and whereas t-LTP is blocked by antagonists at GluN2A and GluN2B subunit-containing NMDA receptors, t-LTD is blocked by GluN2C or GluN2D subunit-preferring NMDA receptor antagonists. Both t-LTP and t-LTD require postsynaptic Ca(2+) for their induction. Induction of t-LTD also requires metabotropic glutamate receptor activation, phospholipase C activation, postsynaptic IP3 receptor-mediated Ca(2+) release from internal stores, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signaling, possibly via release of the gliotransmitter d-serine. We furthermore found that presynaptic calcineurin is required for t-LTD induction. t-LTD is expressed presynaptically as indicated by fluctuation analysis, paired-pulse ratio, and rate of use-dependent depression of postsynaptic NMDA receptor currents by MK801. The results show that CA3-CA1 synapses display both NMDA receptor-dependent t-LTP and t-LTD during development and identify a presynaptic form of hippocampal t-LTD similar to that previously described at neocortical synapses during development.

Dataset Information

Postsynaptic p47phox regulates long-term depression in the hippocampus.

Publications

Postsynaptic p47phox regulates long-term depression in the hippocampus.

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