Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability

Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
Experimental Neurology (Impact Factor: 4.7). 06/2008; 211(1):141-9. DOI: 10.1016/j.expneurol.2008.01.016
Source: PubMed


Caloric restriction (CR) is a daily reduction of total caloric intake without a decrease in micronutrients or disproportionate reduction of any one dietary component. CR can increase lifespan reliably in a wide range of species and appears to counteract some aspects of the aging process throughout the body. The effects on the brain are less clear, but moderate CR seems to attenuate age-related cognitive decline. Thus, we determined the effects of age and CR on key synaptic proteins in the CA3 region of the hippocampus and whether these changes were correlated with differences in behavior on a hippocampal-dependent learning and memory task. We observed an overall, age-related decline in the NR1, N2A and N2B subunits of the N-methyl-d-aspartate (NMDA)-type and the GluR1 and GluR2 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-type ionotropic glutamate receptors. Interestingly, we found that CR initially lowers the glutamate receptor subunit levels as compared to young AL animals, and then stabilizes the levels across lifespan. Synaptophysin, a presynaptic vesicle protein, showed a similar pattern. We also found that both CR and ad libitum (AL) fed animals exhibited age-related cognitive decline on the Morris water maze task. However, AL animals declined between young and middle age, and between middle age and old, whereas CR rats only declined between young and middle age. Thus, the decrease in key synaptic proteins in CA3 and cognitive decline occurring across lifespan are stabilized by CR. This age-related decrease and CR-induced stabilization are likely to affect CA3 synaptic plasticity and, as a result, hippocampal function.

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    • "Interestingly, CR is associated with greater electrical and synaptic activity throughout neuronal circuits when compared to satiated and resting states [43]. In addition, CR stabilizes the levels of glutamate receptors and synaptic proteins required for excitatory transmission and thought to underlie hippocampal-dependent learning and memory [43] [44]. The generation of neurotrophic factors is another important adaptive and neuroprotective response to CR [45]. "
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    • "Both of these brain regions exhibit high responsiveness to the beneficial effects of DR. Studies on the rodent central nervous system (CNS) have revealed that long-term DR can improve learning and memory, and diminish age-related behavioral impairments and cognitive decline (Means et al. 1993; Halagappa et al. 2007; Adams et al. 2008) caused by disruptions of the pivotal brain functions associated with the cortex and hippocampus. Furthermore, DR alleviates t he decline in hippocampal neurogenesis (Park et al. 2013) and counteracts the age-related decrease of synaptic plasticity (Fontán- Lozano et al. 2008; Mladenovic Djordjevic et al. 2010). "
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