Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

Abstract

The brain is a metabolically active organ exhibiting high oxygen consumption and robust production of reactive oxygen species (ROS). The large amounts of ROS are kept in check by an elaborate network of antioxidants, which sometimes fail and lead to neuronal oxidative stress. Thus, ROS are typically categorized as neurotoxic molecules and typically exert their detrimental effects via oxidation of essential macromolecules such as enzymes and cytoskeletal proteins. Most importantly, excessive ROS are associated with decreased performance in cognitive function. However, at physiological concentrations, ROS are involved in functional changes necessary for synaptic plasticity and hence, for normal cognitive function. The fine line of role reversal of ROS from good molecules to bad molecules is far from being fully understood. This review focuses on identifying the multiple sources of ROS in the mammalian nervous system and on presenting evidence for the critical and essential role of ROS in synaptic plasticity and memory. The review also shows that the inability to restrain either age- or pathology-related increases in ROS levels leads to opposite, detrimental effects that are involved in impairments in synaptic plasticity and memory function. Antioxid. Redox Signal. 14, 2013–2054. Introduction Basic Components of Learning and Memory Sources of Reactive Oxygen Species The mitochondrial respiratory chain Complexes I and III Mitochondrial superoxide in learning and memory Monoamine oxidase NOS: NO (and related gases) NADPH oxidase Structure and regulation of the NADPH oxidase NADPH oxidase in the brain NADPH oxidase in synaptic plasticity Physiological Roles of ROS Synaptic signaling and LTP Learning and memory Pathological Release and Effects of ROS ROS in physiological aging ROS in AD ROS during hypoxia/ischemia and traumatic brain injury ROS in multiple disease states Parkinson's disease Diabetes Homocysteinuria Antioxidant Defenses Against Pathological ROS Antioxidant enzymes Superoxide dismutases Synaptic plasticity and memory in young mice Synaptic plasticity and memory in the aged and diseased brain Catalase GPx, glutathione reductase, and related enzymes Metallothionein Antioxidant molecules (nonenzymatic) Ascorbate (vitamin C) Tocopherol (vitamin E) Glutathione Coenzyme Q Carotenoids Melatonin Melatonin and LTP Melatonin and learning and memory (1) Alzheimer's disease 2036 (2) Alcohol poisoning 2036 (3) Excitotoxicity=trauma=ischemia 2037 (4) Other Lipoic acid Minerals Selenium Zinc Manganese Conclusions