Dietary Supplementation with Vitamin E Reverses the Age-related Deficit in Long Term Potentiation in Dentate Gyrus

Abstract

Long term potentiation (LTP) in dentate gyrus is impaired in aged rats, and this has been associated with an age-related decrease in membrane arachidonic acid concentration. In this study, we considered whether the trigger for this age-related decrease in arachidonic acid might be increased lipid peroxidation stimulated by the proinflammatory cytokine, interleukin-1␤. Groups of aged and young rats were fed on a control diet or a diet supplemented with ␣-tocopherol and assessed for their ability to sustain LTP. Aged rats fed on the control diet exhibited an impaired ability to sustain LTP and analysis of tissue prepared from these rats exhibited increased interleukin-1␤, increased lipid peroxidation, and decreased membrane arachidonic acid concentration compared with young rats fed on either diet. Aged rats fed on the supplemented diet sustained LTP in a manner indistinguishable from young rats, and the agerelated increases in interleukin-1␤ and lipid peroxidation and the decrease in membrane arachidonic acid concentration were all reversed. We propose that interleukin-1␤ may be the trigger that induces these agerelated changes and may therefore be responsible for the deficit in long term potentiation in aged rats. The observation that ␣-tocopherol reverses these changes is consistent with the hypothesis that some age-related changes in hippocampus might derive from oxidative stress.Aging is associated with compromised neuronal activity, perhaps typified by a deficit in cognitive function. One particular age-related impairment in neuronal function in the rat is a decrease in ability to sustain long term potentiation (LTP 1 ; Refs. 1-5), which is a putative biological substrate for cognitive function and a model for learning and/or memory. Evidence suggests that a cascade of biochemical changes, initiated by activation of the N-methyl-D-aspartate subtype of glutamate receptor is required to support this form of synaptic plasticity in the dentate gyrus (6). Although the underlying cause of the age-related impairment in ability to sustain LTP is not known, down-regulation of several components of the biochemical cascade has been identified in aged rats. Thus, N-methyl-D-aspartate receptor activity is compromised with age (e.g. Ref. 7), whereas down-regulation of other factors that play a role in induction of LTP, like calcium handling by cells (1) and activation of enzymes such as phospholipase A 2 (3) and protein kinases (8), has been reported. Similarly, factors that play a role in maintenance of LTP, like increased glutamate release, have also been shown to be compromised in hippocampus of aged rats (3,5,9). In addition, the more persistent aspects of LTP, which rely on increased synthesis of new proteins (10 -12) and morphological changes (13), are also impaired in the hippocampus of aged rats (12,14). Despite this immense body of data, the underlying cause of the impairment in ability of aged rats to sustain LTP is not known.One unifying cause of the age-related changes in biochemical parameters might be a chan...

The Anti-inflammatory Cytokine, Interleukin (IL)-10, Blocks the Inhibitory Effect of IL-1β on Long Term Potentiation

“…We argued that if increased JNK activation and decreased glutamate release are responsible for IL-1␤-induced inhibition of LTP, then IL-10, which reverses these effects of IL-1␤ in vitro, should block the inhibitory effect of IL-1␤ on LTP. The data presented here confirm our previous observations that IL-1␤ inhibits LTP (12)(13)(14)16) and demonstrate that IL-10 acts in a dose-dependent manner to abrogate this effect of IL-1␤. We propose that the inhibitory effect of IL-10 on IL-1␤-induced changes in vitro suggests that IL-10 may mediate its effect by blocking the stimulatory effect of IL-1␤ on JNK and its inhibitory effect on glutamate release.…”

“…These effects include modulation of thermoregulation, sleep, and appetite, which are perhaps consistent with the relatively high expression of the signal-generating IL-1 type 1 receptors (IL-1R1) in hypothalamus (1)(2)(3)(4)(5). However, IL-1␤ also inhibits transmitter release (6,7) and calcium channel activity (7,8) in the hippocampus, and it has been shown to inhibit long term potentiation (LTP) in CA1, CA3, and dentate gyrus in vitro (9 -11) and in dentate gyrus in vivo (12)(13)(14)(15); these effects are consistent with the high distribution of IL-1R1 in hippocampus (1)(2)(3)(4)(5). The inhibitory effects of IL-1␤ in hippocampus have been linked with stimulation of the stress-activated kinases, p38 and JNK (14,16), which have also been shown to be activated by IL-1␤ in other cells (17)(18)(19)(20).…”

“…The effect of H 2 O 2 administration on LTP in vivo or its effect in dentate gyrus has not been reported previously, although it has been shown to inhibit LTP in guinea pig CA1 in vitro (51), and we have previously coupled an increase in reactive oxygen species accumulation with a compromise in LTP in dentate gyrus of aged rats and following intracerebroventricular injection of IL-1␤ (12,13). The present data indicate that IL-10 blocked the inhibitory effect of H 2 O 2 on LTP.…”

“…LTP was induced unilaterally in perforant path-granule cell synapses as described previously (12,13). Briefly, a bipolar stimulating electrode and an unpopular recording were stereotaxically positioned in the perforant path (4.4 mm lateral to ) and dorsal cell body region of the dentate gyrus (2.5 mm lateral and 3.9 mm posterior to Bregma), respectively.…”

“…Because previous data indicated that IL-1␤ increased reactive oxygen species production in hippocampus (12,13), it seemed reasonable to propose that IL-10 might antagonize this effect. Fig.…”