Redox Signaling in Neurotransmission and Cognition During Aging

Abstract

Significance: Oxidative stress increases in the brain with aging and neurodegenerative diseases. Previous work emphasized irreversible oxidative damage in relation to cognitive impairment. This research has evolved to consider a continuum of alterations, from redox signaling to oxidative damage, which provides a basis for understanding the onset and progression of cognitive impairment. This review provides an update on research linking redox signaling to altered function of neural circuits involved in information processing and memory. Recent Advances: Starting in middle age, redox signaling triggers changes in nervous system physiology described as senescent physiology. Hippocampal senescent physiology involves decreased cell excitability, altered synaptic plasticity, and decreased synaptic transmission. Recent studies indicate N-methyl-d-aspartate and ryanodine receptors and Ca²⁺ signaling molecules as molecular substrates of redox-mediated senescent physiology.

Critical issues: We review redox homeostasis mechanisms and consider the chemical character of reactive oxygen and nitrogen species and their role in regulating different transmitter systems. In this regard, senescent physiology may represent the co-opting of pathways normally responsible for feedback regulation of synaptic transmission. Furthermore, differences across transmitter systems may underlie differential vulnerability of brain regions and neuronal circuits to aging and disease.

Future directions: It will be important to identify the intrinsic mechanisms for the shift in oxidative/reductive processes. Intrinsic mechanism will depend on the transmitter system, oxidative stressors, and expression/activity of antioxidant enzymes. In addition, it will be important to identify how intrinsic processes interact with other aging factors, including changes in inflammatory or hormonal signals. Antioxid. Redox Signal. 28, 1724-1745.

Keywords: Ca2+ signaling; NMDA receptor; aging; cognition; oxidative stress; redox regulation.

FIG. 1.

Altered redox homeostasis, from signal transduction to oxidative damage, over the course of aging. In younger individuals (green box), a brief rise in hydrogen peroxide or nitric oxide acts as a signal by forming reversible disulfide bonds or S-nitrosylation to rapidly and reversibly influence synaptic function. With advancing age (orange box), increased levels of hydrogen peroxide or nitric oxide prolong or constitutively activate these signaling processes, resulting in stable physiological changes (senescent physiology). With advanced age or in neurodegenerative disease (red box), increased levels of highly reactive molecules, superoxide, peroxynitrite, and the hydroxyl radical induce the accumulation of irreversible damage, impairment in mitochondrial function and synaptic transmission, and cell death. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Effects of increased SOD1 expression on oxidative damage, cognition, and LTP. Young (5 months) and aged (20 months) rats received hippocampal viral (adeno-associated virus [AAV]) injections to express human SOD1 or GFP. (A) Western blot illustrating that regardless of age, the viral-mediated expression of human SOD1 (hSOD1, 23 kDa) was not associated with a change in rat SOD1 (rSOD1, 19 kDa) and was associated with a decrease in lipid peroxidation measured by 4-HNE staining. (B) Quantification of Western blot measures for SOD1 expression and 4-HNE staining. Asterisk indicates a significant difference (p < 0.05) between rats that expressed SOD1 and GFP within each age group. (C, D) Performance of middle-aged rats (17 months) examined on the spatial water maze. Acquisition was measured as (C) the number of platform crossings and (D) latency to first platform crossing during a free swim probe trial delivered immediately after training. Compared with middle-aged rats (17 months) that expressed GFP alone (filled bars), expression of SOD1+GFP (gray bars) resulted in an impairment that was rescued by expression of SOD1+CAT (open bars). (C, D) Asterisk indicates a difference relative to SOD1+GFP animals. (E) Time course of LTP. LTP was measured as a change, relative to baseline, in the EPSP, examined 60 min (boxed area) after high-frequency LTP-inducing stimulation (HFS). The bar graph indicates the magnitude of LTP at 60 min. LTP was induced in slices that expressed GFP and SOD1+CAT (asterisk = significant difference from baseline). In contrast, the response for SOD1+GFP animals did not differ from baseline and was decreased relative to GFP controls (pound sign = significant difference from GFP). 4-HNE, 4-hydroxynonenal; CAT, catalase; EPSP, excitatory postsynaptic potential; GFP, green fluorescent protein; LTP, long-term potentiation; SOD, superoxide dismutase. Figures adapted from Lee et al. (152, 153).

FIG. 3.

Redox-mediated NMDA receptor hypofunction during aging. (A) Illustration of the PFV and the NMDAR component of CA3-CA1 field EPSPs recorded from a young rat (left) and the decrease in the EPSP response in an aged rat (right). (B) Input–output curve plotting the stimulation intensity delivered to the CA3 to CA1 fibers and the initial slope of the evoked NMDAR field for young (open circles) and aged (filled circles) animals. (C) Following recording of a stable baseline response, application of the reducing agent, DTT (arrow), markedly increased the NMDAR response for aged animals (filled circles) relative to young (open circles). DTT, dithiothreitol; NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor; PFV, presynaptic fiber volley. Figures adapted from Bodhinathan et al. (31).

FIG. 4.

Age-related NMDA receptor hypofunction is due to an oxidized intracellular redox state. (A) Application of the reduced form of GSH to the extracellular bath did not alter the NMDAR EPSP in aged animals. (B) In contrast, for intracellular recordings, including GSH in the intracellular recording pipette (filled circles) increased the NMDAR response. This increase was not observed under control conditions (open circles). Figures adapted from Bodhinathan et al. (31). GSH, glutathione.

FIG. 5.

Redox regulation of NMDA receptor function is linked to CaMKII. (A) Inhibition of CaMKII with Myr-AIP blocked the ability of DTT to increase the NMDAR field potential EPSP in aged animals. (B) Inhibition of PKC with Bis-I failed to block the DTT-mediated growth of NMDAR synaptic potential. (C) CaMKII activity is increased by DTT in an age-dependent manner. The control condition for each age group involved 0 DTT and 2.5 mM Ca²⁺. Asterisk indicates difference relative to the control within each age group. CaMKII, Ca²⁺/calmodulin-dependent protein kinase II. Figures adapted from Bodhinathan et al. (31).

FIG. 6.

An oxidized redox state mediates the age-related increase in sAHP. (A) Illustration of sAHP elicited by a 100 ms depolarization to evoke five action potentials. The dashed line indicates that under control conditions (dark traces), sAHP is larger for aged animals. Application of DTT (gray traces) reduced sAHP in aged animals such that the amplitude was similar to that in young. (B) Time course of the change in sAHP following DTT application. Note that DTT decreased sAHP by ∼50% in aged (filled circles), but not in young (open circles), animals. (C) Application of X/XO increased the sAHP amplitude in young animals. sAHP, slow afterhyperpolarization; X/XO, xanthine/xanthine oxidase. Figures adapted from Bodhinathan et al. (32).

FIG. 7.

The age-related increase in sAHP depends on redox regulation of Ca²⁺ release from intracellular stores. Decreasing Ca²⁺ release by (A) depletion of intracellular stores through thapsigargin or (B) RyR blockade prevents the DTT-mediated decrease in sAHP. (C) Blockade of VDCCs with nifedipine failed to inhibit the effects of DTT. RyRs, ryanodine receptors; VDCCs, voltage-dependent Ca²⁺ channels. Figures adapted from Bodhinathan et al. (32).

FIG. 8.

Molecular mechanisms for progression from normal to senescent physiology and neurotoxicity with increasing oxidative stress. (A) Binding of glutamate and postsynaptic depolarization results in NMDAR activation and an influx of Ca²⁺ to induce LTP. The increase in intracellular Ca²⁺ initiates a modest and reversible increase in ROS, nitric oxoide (NO), and/or hydrogen peroxide (H₂O₂). In turn, ROS interacts with redox-sensitive cysteines to induce reversible formation of disulfide bonds, S-glutathionylation, or S-nitrosylation (SNO), inhibiting NMDAR activity. The temporary reduction in NMDAR activity may permit the stabilization of synaptic plasticity during learning. If ROS levels are prolonged, NMDARs remain hyporesponsive due to redox changes at the NMDAR and reduced activity of CaMKII. Similar redox modifications of RyRs increase release of Ca²⁺ from ICS, increasing the amplitude of sAHP. In turn, the sustained hyperpolarizing response further inhibits voltage-dependent NMDAR activation, contributing to impaired LTP induction. (B) As oxidative stress increases, lipid peroxidation and the formation of 4-HNE may have effects on NMDARs and VDCCs that result in a further dysregulation of Ca²⁺ homeostasis. In addition, increased levels of superoxide and the formation of peroxynitrite produce oxidative damage of vulnerable molecules, resulting in an irreversible inhibitory action on proteins and neurotoxicity. ICS, intracellular Ca²⁺ stores; ROS, reactive oxygen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars