ABSTRACT
Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-d-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91
phox
and p47
phox
, both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91
phox
and p47
phox
mutant mice have mild impairments in hippocampus-dependent memory. The gp91
phox
mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47
phox
mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD.
Leptin Enhances NMDA Receptor Function and Modulates Hippocampal Synaptic Plasticity
