Age and ketogenic diet have dissociable effects on synapse-related gene expression between hippocampal subregions

Abstract

As the number of individuals living beyond the age of 65 is rapidly increasing, so is the need to develop strategies to combat the age-related cognitive decline that may threaten independent living. Although the link between altered neuronal signaling and age-related cognitive impairments is not completely understood, it is evident that declining cognitive abilities are at least partially due to synaptic dysfunction. Aging is accompanied by well-documented changes in both excitatory and inhibitory synaptic signaling across species. Age-related synaptic alterations are not uniform across the brain, however, with different regions showing unique patterns of vulnerability in advanced age. In the hippocampus, increased activity within the CA3 subregion has been observed across species, and this can be reversed with anti-epileptic medication (Bakker et al., 2012). In contrast to CA3, the dentate gyrus shows reduced activity with age and declining metabolic activity. Ketogenic diets have been shown to decrease seizure incidence and severity in epilepsy, improve metabolic function in diabetes type II, and improve cognitive function in aged rats. This link between neuronal activity and metabolism suggests that metabolic interventions may be able to ameliorate synaptic signaling deficits accompanying advanced age. We therefore investigated the ability of a dietary regimen capable of inducing nutritional ketosis and improving cognition to alter synapse-related gene expression across the dentate gyrus, CA3 and CA1 subregions of the hippocampus.Following 12 weeks of a ketogenic or calorie-matched standard diet, RTq-PCR was used to quantify expression levels of excitatory and inhibitory synaptic signaling genes within CA1, CA3 and dentate gyrus. While there were no age or diet-related changes in CA1 gene expression, expression levels were significantly altered within CA3 by age and 3 within the dentate gyrus by diet for several genes involved in presynaptic glutamate regulation and postsynaptic excitation and plasticity. These data demonstrate subregionspecific alterations in synaptic signaling with age and the potential for a ketogenic diet to alter these processes in dissociable ways across different brain structures that are uniquely vulnerable in older animals.4 Introduction:

Beta-Hydroxybutyrate Counteracts the Deleterious Effects of a Saturated High-Fat Diet on Synaptic Ampa Receptors and Cognitive Performance

“…It has only been described that KD-mediated improvement in short-term memory in young rodents led to increased GluA1 levels in the HPC, with no changes in GluA2 [31]. At the same time, in adults, KD reduced the expression of GluA1, GluA2, and GluA4-coding genes, yet the impact on cognition was not assessed by [32]. Here, we depicted that BHB treatment increased surface GluA1 levels in cultured neurons without affecting synaptic incorporation.…”

Effects of caloric restriction on the antagonistic and integrative hallmarks of aging

“…KD-fed rats show better performance on a bi-conditional association test, which requires the use of both brain regions (Hernandez et al, 2018). Also in rats, KDs change the gene expression levels in the CA3 region of hippocampus, which is known to impact cognitive abilities during brain aging (Hernandez et al, 2019). These data suggest that KD have the potential to impact the aging brain.…”