LTP and LTD in the Visual Cortex Require the Activation of NOX2

Abstract

Reactive oxygen species (ROS) are signaling factors involved in many intracellular transduction pathways. In the nervous system, ROS are thought to modulate various mechanisms of synaptic plasticity. One important source of ROS production in the brain is the NADPH oxidase complex. Stimulation of NMDA receptors activates NADPH oxidase, which provides selective oxidative responses accompanying the induction of synaptic changes. The activity of NADPH oxidase is known to be crucial for the induction of LTP in the hippocampus. However, the involvement of this complex in cortical synaptic plasticity is still unclear. Here we provide evidence that genetic ablation of NOX2 (the prototypical member of NADPH oxidase family of proteins) suppresses LTP and LTD in the primary visual cortex of the mouse. We also found that the involvement of NOX2 on LTP is partially age-dependent, as the activity of this complex is not critical for mechanisms of synaptic potentiation occurring in immature animals. Furthermore, we show that inhibition of NOX2 reduces the NMDA receptor function, suggesting a possible mechanism that could be the basis of the effects on synaptic plasticity.

Metaplasticity in the Visual Cortex: Crosstalk Between Visual Experience and Reactive Oxygen Species

“…Considering ROS as highly reactive and diffusible molecules, NOX2 activation could be involved in the metaplastic regulation of synaptic changes. In agreement with this idea, previous studies demonstrated that nonfunctional NOX2 impairs synaptic plasticity in the hippocampus and visual cortex (Kishida et al, 2006;De Pasquale et al, 2014).…”

“…In a previous work, it was shown that synaptic plasticity is impaired in gp91 phoxϪ/Ϫ mice and that this is due to a deficiency in NMDAR functioning (De Pasquale et al, 2014). However, here, we demonstrated that plasticity "reopens" in the direction of LTD when gp91 phoxϪ/Ϫ animals are reared in the dark.…”

“…The LTP and LTD of visual cortical supragranular layers require the activation of NMDARs (Kirkwood and Bear, 1995;Philpot et al, 2003Philpot et al, , 2007Yoshimura et al, 2003;Jiang et al, 2007;Smith et al, 2009;Li and Wang, 2013;De Pasquale et al, 2014). Therefore, NOX2 inhibition and visual deprivation may interact to alter the profile of NMDAR-dependent plasticity to favor LTD over LTP according to our hypothesis.…”

“…The first step was to evaluate how dark rearing and genetic suppression of NOX2 modulate the plasticity curve, in which synaptic change is expressed as a function of the postsynaptic depolarization applied during the induction protocol. In our previous study, we found that, in knock-out animals for the NOX2 enzyme (gp91 phoxϪ/Ϫ ), the induction of LTP and LTD was impaired through inhibition of NMDAR activity (De Pasquale et al, 2014). Because deprivation of experience potentiates the NMDAR function (Yoshimura et al, 2003;Guo et al, 2012), we hypothesized that dark exposure could rescue the deficit in plasticity caused by the lack of functional NOX2.…”

“…In the hippocampus and cerebral cortex, NOX enzymes are highly expressed in dendritic synaptic sites and participate in postsynaptic intracellular pathways important for plasticity (Serrano et al, 2003;Kim et al, 2005;Tejada-Simon et al, 2005;Massaad and Klann, 2011). The NOX2 isoform is stimulated by NMDAR activation and this event produces large and controlled amounts of superoxide in a rapid process that links extracellular stimuli to subsequent signaling processes (Bindokas et al, 1996;Kishida et al, 2005;Brennan et al, 2009;Girouard et al, 2009;Guemez-Gamboa et al, 2011;Reyes et al, 2012;De Pasquale et al, 2014). Although the physiological roles of NOX2 in the brain are only partially understood, it has been proposed that one of its functions could be the redox modulation of neurotransmission and plasticity at glutamatergic synapses (Sorce and Krause, 2009;Sorce et al, 2010).…”