Ketogenic Diets Cause Opposing Changes in Synaptic Morphology in CA1 Hippocampus and Dentate Gyrus of Late-Adult Rats

Abstract

Ketogenic diets (KDs) have beneficial effects on several diseases, such as epilepsy, mitochondriopathies, cancer, and neurodegeneration. However, little is known about their effects on aging individuals. In the present study, late-adult (19-month-old) rats were fed for 8 weeks with two medium chain triglycerides (MCT)-KDs, and the following morphologic parameters reflecting synaptic plasticity were evaluated in stratum moleculare of hippocampal CA1 region (SM CA1) and outer molecular layer of hippocampal dentate gyrus (OML DG): average area (S), numeric density (Nv(s)), and surface density (Sv) of synapses, and average volume (V), numeric density (Nv(m)), and volume density (Vv) of synaptic mitochondria. In SM CA1, MCT-KDs induced the early appearance of the morphologic patterns typical of old animals (higher S and V, and lower Nv(s) and Nv(m)). On the contrary, in OML DG, Sv and Vv of MCT-KDs-fed rats were higher (as a result of higher Nv(s) and Nv(m)) versus controls; these modifications are known to improve synaptic function and metabolic supply. The opposite effects of MCT-KDs might reflect the different susceptibility to aging processes: OML DG is less vulnerable than SM CA1, and the reactivation of ketone bodies uptake and catabolism might occur more efficiently in this region, allowing the exploitation of their peculiar metabolic properties. Present findings provide the first evidence that MCT-KDs may cause opposite morphologic modifications, being potentially harmful for SM CA1 and potentially advantageous for OML DG. This implies risks but also promising potentialities for their therapeutic use during aging.

A ketogenic diet increases succinic dehydrogenase (SDH) activity and recovers age-related decrease in numeric density of SDH-positive mitochondria in cerebellar Purkinje cells of late-adult rats

“…Finally, it is interesting to compare present data with those previously obtained, with the same KD, on synapses and synaptic mitochondria in the stratum molecular of hippocampal CA1 pyramidal cells (SM CA1) and in the outer molecular layer of the hippocampal granular cells (OML DG) (Balietti et al, 2008) as well as in the glomerular layer of the cerebellar cortex (GL-CCx) (Balietti et al, 2009b). In PC and OML DG positive effects were displayed, in GL-CCx no changes were found, while in SM CA1 harmful consequences were observed.…”

“…During aging, the plastic reactivity needed to face the metabolic challenge may be even more impaired, but only a few data are available on this matter. Recently, we have examined the consequences of two medium chain triglycerides (MCT)-KDs on the ultrastructural features of hippocampal and cerebellar synapses and synaptic mitochondria of late-adult rats, and we have provided the first evidence that the ketogenic approach offers promising potentialities along with not negligible risks: the effects may be even opposite in different brain regions, depending critically on neuronal vulnerability to age and on daily ketogenic intake (Balietti et al, 2008;Balietti et al, 2009b). Further investigation in aged animals is required to evaluate whether positive results found in younger organisms can be at least partly replicated, and whether potential side-effects associated with the therapeutic use can be reduced.…”

The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury

“…Differential synaptic changes have been observed in senescent rats after 8 weeks of 10 or 20% medium chain triglyceride diet (Bioserv) ( 58 ). In these aged rats, the diet showed opposing morphologic modifi cations with the stratum moleculare layer of Cornu Ammonis (CA)1, showing lower synaptic density and fewer synaptic mitochondria, while the outer molecular layer of the dentate gyrus showed greater synaptic density and mitochondrial concentrations.…”

Neuroprotection in metabolism-based therapy

“…In late-adult rats, medium chain triglyceride diet (10 and 20% MCT) exposure for 8 weeks was associated with an increased density of synapses and synaptic mitochondria in neurons in the outer molecular layer of the dentate gyrus (an ‘anti-aging’ effect), but in contrast, these parameters were decreased in neurons from the stratum molecular of the CA1 region (an ‘accelerated aging’ effect) (Balietti et al, 2008). After exposure to the 20% MCT diet, these rats showed an increase in numerical density of succinate dehydrogenase-positive mitochondria in Purkinje cells from the cerebellar vermis (an area that shows age-related degeneration) (Balietti et al, 2010).…”