Sources and targets of reactive oxygen species in synaptic plasticity and memory

Abstract

Increasing evidence suggests that reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, act as necessary signaling molecules in processes underlying cognition. Moreover, ROS have been shown to be necessary in molecular process underlying signal transduction, synaptic plasticity, and memory formation. Research from several laboratories suggests that NADPH oxidase is an important source of superoxide in the brain. Evidence is presented here to show that ROS are in fact important signaling molecules involved in synaptic plasticity and memory formation. Moreover, evidence that the NADPH oxidase complex is a key regulator of ROS generation in synaptic plasticity and memory formation is discussed. Understanding redox signaling in the brain, including the sources and molecular targets of ROS, are important for a full understanding of the signaling pathways that underlie synaptic plasticity and memory. Knowledge of ROS function in the brain also is critical for understanding aging and neurodegenerative diseases of the brain given that several of these disorders, including Alzheimer's disease and Parkinson disease, may be exacerbated by the unregulated generation of ROS.

FIG. 1. Subunit composition and activation of the NADPH oxidase complex

(A) The NADPH oxidase complex consists of two membrane bound subunits (gp91^phox and p22^phox) and three cytosolic subunits (p67^phox, rac, and p47^phox), which upon activation translocate and associate with the membrane bound subunits (B). Upon activation, the NADPH oxidase complex transfers electrons from NADPH substrate to molecular oxygen, thus producing superoxide. During this process NADPH oxidase also pumps protons across the membrane.

FIG. 2. Schematic depicting the role of ROS in the molecular mechanisms underlying cognition

(A) Low concentrations of ROS are required for signaling, synaptic plasticity, and memory formation; however, as the concentration of ROS increases, their function switches from a signaling molecule to an inhibitory or even toxic molecule. (B) On the left: superoxide and H₂O₂ activate protein kinase C (PKC) and extracellular-signal regulated kinase (ERK) and oxidize neurogranin (NG), which then releases calmodulin, resulting in the activation of calcium/calmodulin-dependent protein kinase II (CaMKII). On the right: superoxide and H₂O₂ also inhibit calcineurin (a.k.a. protein phosphatase 2B, PP2B). Activation of PKC, ERK, and CaMKII promote LTP, whereas the activity of PP2B tends to block LTP; thus activation of PKC, ERK, and CaMKII, along with the inhibition PP2B are all plausible, redox-sensitive, mechanisms by which ROS could promote synaptic plasticity in a concentration-dependent and cellular signaling state-dependent manner.