Synaptic Plasticity Deficits and Mild Memory Impairments in Mouse Models of Chronic Granulomatous Disease

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.Chronic granulomatous disease (CGD) is caused by inherited mutations in genes encoding subunits of the NADPH oxidase complex (7,14,36,43). NADPH oxidase is composed of two membrane-bound subunits (gp91 phox and p22 phox ) and three cytosolic subunits, which include p47 phox , p67 phox , and Rac (49). The membrane-bound subunits form a heterodimer that stabilizes them within the membrane, whereas the cytosolic subunits are recruited to the membrane following stimulation. Complete complex assembly is necessary for full NADPH oxidase activity (2). Mutations in the gp91 phox and p47 phox genes are the most common mutations that cause CGD (58). These mutations disable the NADPH oxidase complex, thereby preventing the oxidation of NADPH and the subsequent production of superoxide (31, 45), which is required for pathogen destruction as well as most superoxide-dependent signal transduction in nonphagocytic cells (21,24,49).CGD patients suffer from frequent bacterial and fungal infections and inflammatory granulomas in the lungs, liver, skin, lymph nodes, and lining of the gastrointestinal and genitourinary tracts (34); loss of phagocytic oxidative burst activity due to mutations in genes encoding the NADPH oxidase subunits is the cause of these symptoms. gp91 phox (40) and p47 phox (22) mutant mice have been generated and used as models for the most common mutations that cause CGD. These mutant mouse lines, which lack their respective gene products due to targeted homologous recombinant gene disruption, have been utilized to understand the molecular mechanisms underlying CGD (22,40).NADPH oxidase has been studied primarily for its role in the phagocyte oxidative burst in the immune system (43); ho...

Superoxide-Induced Potentiation in the Hippocampus Requires Activation of Ryanodine Receptor Type 3 and ERK

“…The only one of the aforementioned sources directly linked to synaptic plasticity and learning and memory is NADPH oxidase. Pharmacological inhibitors of NADPH oxidase blocked LTP and NMDA receptor-dependent activation of ERK in area CA1 of the hippocampus (Kishida et al 2005(Kishida et al , 2006. LTP also was abolished in mice lacking either one of two subunits, gp91 phox or p47 phox , critical for NADPH oxidasedependent superoxide production (Kishida et al 2006).…”

“…Pharmacological inhibitors of NADPH oxidase blocked LTP and NMDA receptor-dependent activation of ERK in area CA1 of the hippocampus (Kishida et al 2005(Kishida et al , 2006. LTP also was abolished in mice lacking either one of two subunits, gp91 phox or p47 phox , critical for NADPH oxidasedependent superoxide production (Kishida et al 2006). These mice display mild deficits in hippocampus-dependent memory tasks as well (Kishida et al 2006).…”

“…LTP also was abolished in mice lacking either one of two subunits, gp91 phox or p47 phox , critical for NADPH oxidasedependent superoxide production (Kishida et al 2006). These mice display mild deficits in hippocampus-dependent memory tasks as well (Kishida et al 2006). Thus NADPH oxidase is likely one of the sources of superoxide required for LTP and memory function.…”

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

“…Reactive oxygen species (ROS) are chemically reactive molecules that modulate signal transduction pathways involved in synaptic plasticity Klann and Thiels, 1999;Knapp and Klann, 2002;Kishida et al, 2005Kishida et al, , 2006Kishida and Klann, 2007). During brain function, one of the main sources of ROS is the NADPH oxidase complex (Infanger et al, 2006;Bedard and Krause, 2007).…”

“…Specifically, NADPH oxidase is known to be activated by NMDA receptor (NMDAR) stimulation (Kishida et al, 2005;Brennan et al, 2009). This makes this complex particularly suited to provide high amounts of ROS during the induction of synaptic plasticity.…”