Caloric restriction eliminates the aging-related decline in NMDA and AMPA receptor subunits in the rat hippocampus and induces homeostasis

Abstract

Caloric restriction (CR) extends life span and ameliorates the aging-related decline in hippocampal-dependent cognitive function. In the present study, we compared subunit levels of NMDA and AMPA types of the glutamate receptor and quantified total synapses and multiple spine bouton (MSB) synapses in hippocampal CA1 from young (10 months), middle-aged (18 months), and old (29 months) Fischer 344xBrown Norway rats that were ad libitum (AL) fed or caloric restricted (CR) from 4 months of age. Each of these parameters has been reported to be a potential contributor to hippocampal function. Western blot analysis revealed that NMDA and AMPA receptor subunits in AL animals decrease between young and middle age to levels that are present at old age. Interestingly, young CR animals have significantly lower levels of glutamate receptor subunits than young AL animals and those lower levels are maintained across life span. In contrast, stereological quantification indicated that total synapses and MSB synapses are stable across life span in both AL and CR rats. These results indicate significant aging-related losses of hippocampal glutamate receptor subunits in AL rats that are consistent with altered synaptic function. CR eliminates that aging-related decline by inducing stable NMDA and AMPA receptor subunit levels.

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

“…Finally, the functional enrichments of the genes obtained from the network analysis were characterized by investigating over-represented gene ontology biological processes and pathways Marchal et al 2013), our method was also able to uncover the effect of both interventions on unrecognized molecular processes such as those related to synaptic transmission and glutamatergic signaling. In particular, they suggest the involvement of glutamatergic ionotropic receptors, including AMPA receptor subunits 1, 2 and 3 (GRIA1, 2 and 3), a result reported in connection with CR in rats (Shi et al 2007) and very recently confirmed also in mice (Schafer et al 2015). The involvement of these key signaling molecules for brain functions reinforces the notion that dietary interventions such as those studied herein hold the ability to modulate brain health and function.…”

Age- and calorie restriction-related changes in rat brain mitochondrial DNA and TFAM binding

“…Additional studies, performed in different areas of the rat brain, including some cortical regions, support the hypothesis about the attenuation of some age-induced alterations by CR (Kaur et al 2008;Shi et al 2007). In particular, Shi et al (2007) identified a brain-specific possible mechanism of CR action through the induction of stability or homeostasis of some crucial neural parameters, usually declining with aging. Such CR-induced homeostasis should involve an enhanced defense also against external insults as the age-related, accumulating oxidative stress.…”

“…Support for the protective action by CR on mitochondrial functions comes from the data by Sanz et al (2005), showing that CR in brain mitochondria reduces the age-related increased production of ROS at complex I (20 % decrease) by improving the efficiency of mitochondria in avoiding electron leaks at that complex as well as from other studies (Aspnes et al 1997;Barja 2007;Bua et al 2004;Cassano et al 2004Cassano et al , 2006Kang et al 1998;Quintas et al 2012;Stuart et al 2004). Additional studies, performed in different areas of the rat brain, including some cortical regions, support the hypothesis about the attenuation of some age-induced alterations by CR (Kaur et al 2008;Shi et al 2007). In particular, Shi et al (2007) identified a brain-specific possible mechanism of CR action through the induction of stability or homeostasis of some crucial neural parameters, usually declining with aging.…”

Contributions of impaired hippocampal plasticity and neurodegeneration to age-related deficits in hormonal pulsatility

“…Changes in levels of several different neurotransmitter and/or their receptors have been reported including: decreased levels of acetylcholine and decreased sensitivity of muscarinic receptors to acetylcholine (Lippa et al, 1982;Perry et al, 1993); alterations in levels of NMDA and AMPA glutamate receptors (Shi et al, 2007); and decreased serotonergic input to the hippocampus (Luellen et al, 2007). In addition, neurotrophic support of hippocampal neurons may be diminished during aging as suggested by a decline in the expression of brain-derived neurotrophic factor (BDNF) (Adlard et al, 2005;Luellen et al, 2007) and insulin-like growth factor 1 (IGF-1) (Sonntag et al, 1999).…”