Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity

Abstract

In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated.

Keywords: oxidative stress; reactive oxygen species; synaptic plasticity.

Figure 1

Physiological effects of ROS on synaptic plasticity. NMDA receptor stimulation (1) during normal brain activity results in calcium influx. Neural nitric oxide synthase (nNOS) is activated (2) through the Ca²⁺-dependent pathway involving calmodulin. Stimulation of nNOS leads to controlled bursts of superoxide production from NADPH oxidase (3) via protein kinase G (PKG). Superoxide is rapidly transmuted to H₂O₂, which pass the membrane and participate in various cellular processes. H₂O₂ and calcium are required for the recruiting of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) (4). H₂O₂ also facilitates the calmodulin-dependent activation of neurogranine and calcium calmodulin kinase II (CaMKII) sequentially (5). Nitric oxide (NO) produced by nNOS allows the entrance of Fe²⁺ through interaction with the divalent metal transporter 1 (DMT-1) (6). H₂O₂ and Fe²⁺ react to form the high reactive species OH⁻, which stimulates the ryanodine receptors (RyR) allowing the liberation of calcium from the endoplasmic reticulum (7) amplifying the Ca²⁺ signal. The activity of ERK, PKC, and CaMKII results in AMPA receptor phosphorylation, which is fundamental to increase the number of units in the plasma membrane and increase the receptor efficacy. ERK and CaMKII translocate into the nucleus and activate specific transcription factors such as the cAMP response element-binding protein (CREB) (8). New proteins are synthesized in order to promote long-term changes in synaptic function and synaptic morphology. If dopaminergic modulation occurs, the production of antioxidants is increased (9). Dopamine and D1 receptors form an internalized complex, which reacts with the accumulated ROS as a reducing factor (10). The relative abundance of antioxidant enzymes assures the preponderance of physiological over pathological processes. Antioxidants neutralize the excessive production of ROS, especially those derived from mitochondria (11). In the nucleus, base excision repair (BER) components compensate DNA damage caused by ROS (12).

Figure 2

Pathological effects of ROS on synaptic plasticity. Glutamatergic over stimulation and Aβ oligopeptides sustain NMDA receptor hyperactivation (1). Massive calcium influx (2) leads to NADPH oxidase-mediated superoxide production (3) via activation of calmodulin, neural nitric oxide synthase (nNOS) and protein kinase G (PKG), respectively. Superoxide is converted to H₂O₂, which passes the plasma membranes and accumulates inside the cell (4). H₂O₂ stimulates the L-type voltage-dependent calcium channels (L-VDCC) further increasing the concentration of intracellular calcium (5). H₂O₂ accumulation creates the intracellular redox environment suitable for triggering the phospholipase A2 (PLA2) pathway through recruitment of extracellular signal-regulated kinase (ERK) and interleukin 1β (IL-1β) (6). Activation of PLA2 stimulates the release of arachidonic acid (AA) from the plasma membrane (7). The AA oxidative metabolism in the mitochondria promotes high levels of mitochondrial ROS accumulation (8) and the release of cytochrome C (9), which starts the apoptotic cascade involving caspases proteins. With the relative absence of antioxidant enzymes, excessive H₂O₂ generated by mitochondria reach the nucleus and provoke DNA damage. H₂O₂ facilitates the calmodulin-mediated activation of calcineurin and CaMKII. Calcineurin dephosphorylates protein phosphatase 1 (PP1) (10), which in turn dephosphorylates the AMPA receptor promoting its internalization. CaMKII participates in the down regulation of NMDA receptors (11) by reducing the amount of NR2B subunits in the population of active receptors.