Effects of aging and caloric restriction on dentate gyrus synapses and glutamate receptor subunits

Abstract

Caloric restriction (CR) attenuates aging-related degenerative processes throughout the body. It is less clear, however, whether CR has a similar effect in the brain, particularly in the hippocampus, an area important for learning and memory processes that often are compromised in aging. In order to evaluate the effect of CR on synapses across lifespan, we quantified synapses stereologically in the middle molecular layer of the dentate gyrus (DG) of young, middle aged and old Fischer 344 x Brown Norway rats fed ad libitum (AL) or a CR diet from 4 months of age. The results indicate that synapses are maintained across lifespan in both AL and CR rats. In light of this stability, we addressed whether aging and CR influence neurotransmitter receptor levels by measuring subunits of NMDA (NR1, NR2A and NR2B) and AMPA (GluR1, GluR2) receptors in the DG of a second cohort of AL and CR rats across lifespan. The results reveal that the NR1 and GluR1 subunits decline with age in AL, but not CR rats. The absence of an aging-related decline in these subunits in CR rats, however, does not arise from increased levels in old CR rats. Instead, it is due to subunit decreases in young CR rats to levels that are sustained in CR rats throughout lifespan, but that are reached in AL rats only in old age.

Novel object recognition is not affected by age despite age-related brain changes

“…We chose a strain of rats with known age-related biological changes in the brain [4][5][6]12,25] and a delay period for the novel object recognition task based on studies in which there are age-related deficits in the novel object recognition task [19,26]. Surprisingly our results demonstrated that there was no difference in young and aged rats in the time spent exploring the novel object.…”

“…Thus, in the present study we examined the novel object recognition task at a delay period that has been shown to be impaired in aged rats of two different strains [19,23]. Moreover, we used a strain of rats, F344XBrown Norway, which have published agerelated biological changes in the brain [4][5][6]15,25]. Our data suggest that novel object recognition is not impaired in aged rats although both young and old rats have a demonstrated side preference for the location of the novel object.…”

“…The neurobiological changes in the aging brain underlying these cognitive alterations have been investigated. It is now well documented that significant cell loss in the structures of the medial temporal lobe does not occur with age and thus, does not contribute to the cognitive changes with age [2][3][4][5][6]. Changes in the number of synapses, which are highly labile structures, are responsive to microenvironmental changes in the brain and result in a continual refinement of neuronal circuitry [7,8], may underlie these cognitive changes.…”

“…The current literature has been equivocal as to the direction of change in synapses with age. Some studies have found that synapses decline with age [6,9] and some found no change in the number of synapses [4,5]. Thus, it is very likely that subtle changes in the function of synapses contribute to cognitive declines with age.…”

“…The data about the composition of synapses also are equivocal with respect to age-related changes. Some studies have found changes in key synaptic proteins such as glutamate receptors that underlie synaptic plasticity like long-term potentiation [4][5][6]; some have found no age-related differences [10], and some have found both [11]. Moreover, it has been demonstrated that synaptic function changes with age [12].…”