IMPAIRMENT IN SYNAPTIC PLASTICITY IN THE RAT HIPPOCAMPUS CAN BE REVERSED BY DIETARY MANIPULATION: A ROLE FOR INTERLEUKIN-1
MA Lynch
Department of Physiology, Trinity College,
Dublin 2, Ireland
Age is accompanied by a great number of changes in neuronal function; one of these is a deficit in cognitive function. Consistent with the idea that long-term potentiation (LTP) in the hippocampus may be a biological substrate for learning and/or memory is the observation that, in rats, the deficit in cognition is coupled with a decreased ability of aged rats to sustain LTP. In the past few years, it has been shown that the age-related impairment in LTP is coupled with an increase in the concentration of the proinflammatory cytokine, interleukin-1b (IL-1b) and with an increase in production of reactive oxygen species (ROS) in hippocampus. Current evidence suggests that IL-1b triggers the increase in ROS by enhancing activity of superoxide dismutase (but not glutathione peroxidase or catalase). Among the downstream effects of these changes is upregulation of the stress-activated kinases, JNK and p38 and recent data has revealed that cell death occurs as a consequence of these changes.
We argued that if the increases in IL-1b and ROS production could be
attenuated, then synaptic function might be restored and LTP might be
sustained. To test this hypothesis, young and aged rats were treated for 8-12 weeks with antioxidant vitamins E and C, or with w-3 fatty acids (which have been shown to possess anti-inflammatory properties);
corresponding numbers were untreated and served as controls. At the end of this period, rats were anaesthetized with urethane and were assessed for their ability to sustain LTP in perforant path-granule cell synapses. Tissue was prepared from hippocampus of these animals following electrophysiological recording and used for the assessments described below.
The data indicate that, while control aged rats exhibited the characteristic deficit in LTP, those which received the experimental treatments sustained LTP in a manner comparable to young rats. This restoration of function was accompanied by a reversal of the age-related increases in IL-1b and ROS. In the case of one of the w-3 fatty acids used in the study, eicosapentanoic acid, further investigation was undertaken. The data revealed that, in parallel with its ability to attenuate the age-related increases in IL-1b concentration and ROS accumulation, this treatment also reversed the age-related increase in activities of JNK and p38. The evidence suggested that the age-related increases in JNK and p38 led to activation of caspase-3, an enzyme which has been shown to be involved in apoptotic cell death. Assessment of changes in caspase-3 activity in hippocampal tissue prepared from young and aged rats which
received control treatment or were treated with eicosapentanoic acid,
revealed that the age-related increase in apoptotic cell death was
abrogated by the experimental treatment. The evidence is consistent with the view that IL-1b and/or oxidative stress may trigger a cascade of events which leads to cell death in the hippocampus of aged rats and that treatment with eicosapentanoic acid reverses several of these age-related changes.
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