Reactive oxygen species in the regulation of synaptic plasticity and memory

Cynthia A Massaad, Eric Klann, Cynthia A Massaad, Eric Klann

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.

Figures

FIG. 1.
FIG. 1.
LTP in a rodent hippocampal slice. (A) Experimental setup for a typical LTP experiment in a hippocampal slice. The Schaffer collateral pathway is stimulated and fEPSPs are recorded in stratum radiatum (the dendrites of pyramidal neurons) in area CA1. (B) Sample fEPSPs before and after LTP has been induced by high-frequency stimulation of the Schaffer collaterals. fEPSP, field excitatory postsynaptic potential; CA, cornu ammonis; LTP, long-term potentiation.
FIG. 2.
FIG. 2.
Graph of a typical LTP experiment. A schematic graph representing the slope of the fEPSP in hippocampal slices before and after delivery of high-frequency stimulation (indicated by the arrow) of the Schaffer collateral to induce LTP (indicated by Δ) recorded from the dendrites in stratum radiatum of area CA1. HFS, high-frequency stimulation.
FIG. 3.
FIG. 3.
Essential cellular components of LTP and memory. Stimulation of presynaptic neurons causes the release of glutamate, which activates AMPA, NMDA, and mGluRs, resulting in massive Ca2+ influx and subsequent production of small messenger molecules such as cAMP and cyclic guanosine monophosphate/NO. These messengers activate multiple protein kinase signaling pathways, including CaMKII, PKA, PKC, and ERK, which ultimately result in the phosphorylation of CREB, which in turn recruits multiple transcription coactivators to initiate a wave of transcription/translation. The newly formed proteins modulate synaptic strength and efficacy via altering the electrical properties of membranes, increasing glutamate receptor expression, changing synaptic morphology, increasing the number of synapses etc., all of which are necessary for long-lasting LTP and the formation of long-term memories. In addition to CREB-mediated gene transcription, some components of these signaling cascades, such as NO and neurogranin, directly contribute to the induction and maintenance of LTP. ROS produced at various sites within the cell (as described in the text) are also essential to the induction of LTP and contribute to these signaling cascades at multiple levels by modifying the molecules marked by grey stars. Note that this is a simplified version of the complex signaling involved in LTP and memory formation. Ca2+, calcium; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding protein; ERK, extracellular signal-regulated kinase; mGluR, metabotrobic glutamate receptor; NMDA, N-methyl-d-aspartate; NO, nitric oxide; PKA, protein kinase A; ROS, reactive oxygen species.
FIG. 4.
FIG. 4.
Production of superoxide by mitochondria. A schematic diagram illustrating the various elements of the electron transport chain located in the inner mitochondrial membrane. Note the production of superoxide at complexes I and III. The gray dotted line represents the path of electron transfer through the respiratory chain.
FIG. 5.
FIG. 5.
Production of H2O2 by monoamine oxidase. A schematic diagram illustrating the production of H2O2 from the monoamine oxidase located in the outer mitochondrial membrane. H2O2, hydrogen peroxide.
FIG. 6.
FIG. 6.
Production of nitric oxide by NOS. (A) NOS uses L-arginine and molecular oxygen as precursors to produce NO and L-citrulline. (B) NOS is active as a homodimer and has two domains: an oxygenase domain and a reductase domain. The oxygenase domain contains three bound cofactors (BH4, heme, and zinc) and functions as the active site of the enzyme. The reductase domain contains three cofactors as well (NADPH, FAD, and FMN) and functions primarily in the electron transfer within the enzyme and the regeneration of other cofactors. The oxygenase and reductase domains are linked together via a region that binds calmodulin (CaM), which is required for the activity of the enzyme (and therefore for NO production). (C) Production of peroxynitrite. Peroxinitrite is a short-lived oxidant species formed by the combination of superoxide and nitric oxide radicals. Peroxynitrite anion (ONOO−) is in equilibrium with peroxynitrous acid (ONOOH; pKa = 6.8); both are highly reactive species. Sites of peroxynitrite formation are assumed to be associated with the sources of superoxide (such as the mitochondrial respiratory chain complexes I and III or the NADPH oxidases) because NO is a relatively stable and highly diffusible free radical while superoxide is short-lived and has restricted diffusion across membranes. BH4, tetrahydrobiopterin; NOS, NO synthase.
FIG. 7.
FIG. 7.
Production of superoxide by NADPH oxidase. When NADPH oxidase is inactive, gp91phox and p22phox are membrane-bound while the four remaining subunits, p67phox, p47phox, p40phox, and Rac are cytosolic. Upon stimulation, the cytosolic subunits translocate to the membrane to form a complex with the membrane-bound components. The assembly of all subunits yields an active enzyme that catalyzes the oxidation of NADPH into NADP+, releasing an electron in the process. The electron is coupled to oxygen to generate superoxide. Although gp91phox is the catalytic core of the enzyme, responsible for the transmission of an electron to oxygen, the presence and correct positioning of all subunits is required for full function of the enzyme. GDI, guanine nucleotide dissociation inhibitor; GDP, guanosine diphosphate; Rac, ras-associated C3 botulinum toxin substrate.
FIG. 8.
FIG. 8.
A model for oxidative activation of PKC in LTP. LTP-inducing stimulation results in activation of the NMDA receptor and subsequent Ca2+ influx into the postsynaptic neuron. Ca2+ triggers production of superoxide via NADPH oxidase, which acts directly on cysteine residues in PKC. Oxidation of PKC results in zinc release and autonomously active PKC. It is unknown whether this activation occurs presynaptically or postsynaptically.
FIG. 9.
FIG. 9.
(A) Cellular localization of the three SOD isozymes and the dismutation of superoxide. SODs catalyze the dismutation of the superoxide radical into H2O2. There are three isoforms of SOD. SOD-1 (or Cu/Zn-SOD) is found in all intracellular compartments, including the cytoplasm, the nucleus, lysosomes, and the inner membrane space of mitochondria. SOD-2 (or manganese SOD) is localized primarily in the mitochondrial matrix. SOD-3 (or extracellular SOD) is present mainly in the extracellular space. In the brain, it can also be found on the endothelial cell surface and cytoplasm. (B) Removal of H2O2 by catalase. H2O2 produced in the cell by various reactions, including the dismutation of superoxide by SODs, is converted into water (H2O) by the action of catalase. SOD, superoxide dismutase.
FIG. 10.
FIG. 10.
Schematic representation of the glutathione synthesis and redox system. GSH is a tripeptide synthesized from glutamate, cysteine, and glycine by a two-step reaction requiring ATP. GSH is a major scavenger of H2O2. H2O2 is transformed into two molecules of water (H2O), whereas two GSH molecules are oxidized (GSSG) by the action of the seleno-enzyme glutathione peroxidase. GSSG can be converted back to GSH by the NADPH-dependent glutathione reductase. ATP, adenosine triphosphate; GSH, glutathione; GSSG, oxidized glutathione.
FIG. 11.
FIG. 11.
Vitamin C. Vitamin C (or ascorbate) is an antioxidant molecule that neutralizes free radicals (radical•) by donating an electron and becoming a free radical itself. However, the ascorbate radical is stable due to its resonance structure (shown by the dashed lines in the chemical structure). Vitamin C also is returned readily to its nonradical form via the action of either NADH- or NADPH-dependent reductases. In the presence of metal ions, however, the production of ascorbate radical can become overwhelming. For example, ascorbate acts as an electron acceptor for Fe3+, instead of H2O2, generating an ascorbate radical in the process. Copper ion (Cu2+) can also react with ascorbate, with 80 times more efficiency than Fe3+. Thus, Vitamin C can be a powerful antioxidant as long as metal ions are not present, but small amounts of vitamin C in the presence of metal ions can make vitamin C a dangerous prooxidant. Organisms have developed defenses against this process, such as having iron and copper bound to the transport proteins such as ferritin, transferritin, and caeruloplasmin. However, the exogenous introduction of metal ions from environmental pollutants can cause the failure of this defense mechanism.
FIG. 12.
FIG. 12.
Fenton chemistry. Ferrous iron (II) (Fe2+) is oxidized by H2O2 to produce ferric iron (III)(Fe3+), along with the highly reactive hydroxyl radical (OH•) and a hydroxyl anion (OH−). After the Fenton reaction, Fe3+ can be reduced back to Fe2+ by the action of H2O2 to produce a peroxyl radical (HOO•) and a proton in the process.
FIG. 13.
FIG. 13.
Dual roles for ROS in the brain. Under physiological conditions, ROS act as essential signaling molecules, necessary for the proper synaptic plasticity and normal memory. However, during aging, ischemia, trauma, and neurodegenerative diseases, the levels of ROS increase to levels higher than the antioxidant machinery of the cells can handle. Thus, the beneficial roles of ROS are overwhelmed by the ambiance of oxidative damage that ROS create.
FIG. 14.
FIG. 14.
Why does mitochondrial superoxide impair learning and memory during AD but not during normal aging? In contrast to cytosolic and extracellular superoxide, which contribute to normal synaptic plasticity and memory, mitochondrial superoxide does not appear to impact either normal synaptic plasticity and memory or age-dependent impairments in synaptic plasticity and memory. Perhaps this is due to limited diffusion of mitochondrial superoxide across the mitochondrial membrane. During AD, mitochondrial dysfunction is prevalent, hence increasing the probability for leakage of mitochondrial-produced free radicals through damaged membranes. Thus, mitochondrial superoxide plays a critical role in extreme oxidative stress that occurs during neurodegenerative diseases such AD. AD, Alzheimer's disease.

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