Claudia Carvallo VarasSanto Tomás University, Chile
Title: Cellular and molecular mechanisms of the effect of Intermittent Ketogenic diet on hippocampal synaptic plasticity in aging
Physiological aging is a natural process, which at the brain level is associated with cellular and functional deterioration that precedes a decline in cognitive abilities, mainly in the hippocampus. As life expectancy increases in the population, there is a greater demand for strategies that aim to reverse age-related cognitive decline. Sedentary lifestyles and a diet with excess carbohydrates and saturated fats induce a dysregulated metabolism generating a deterioration in hippocampal synaptic plasticity during age. On the other hand, lifestyles that include bioenergetic challenges such as exercise or fasting favor ?-oxidation to produce ketone bodies that increase the expression of trophic factors (BDNF, brain-derived neurotrophic factor) that promote synaptic plasticity. As we age, antecedents show an increasing vulnerability in function, which translates into the alteration of synaptic plasticity mechanisms at the hippocampal level, which is evidenced by a lower number of glutamatergic receptors, which is correlated with the alteration of cognitive processes such as learning and memory. Recent studies show that an intermittent ketogenic diet (high in fat and without carbohydrates) increases memory in aging animals. The link between energy metabolism and neuronal signaling suggests that metabolic interventions could improve dysregulated synaptic plasticity during aging. Considering this, what is the cellular and molecular mechanism by which an intermittent ketogenic diet improves memory in aging animals? In the present project, we propose that an intermittent ketogenic diet improves cognitive processes and synaptic plasticity by inserting new AMPA receptors in the plasma membrane through changes in their levels of phosphorylation in serines 831 and 845 of the CA1 area of the hippocampus in aged mice. We propose the use of behavioral, electrophysiological, cellular and molecular approaches in hippocampal slices from aged mice of 23 month administered a ketogenic diet. First, we will measure metabolic parameters like BHB, glucose, and triglycerides. Second, we will assess learning and memory through behavioral studies in the Barnes maze and plasticity mechanisms that correlate with learning and memory, such as long-term potentiation (LTP) by field excitatory postsynaptic potentials (fEPSP) records. To determine the specific contribution of the AMPA receptor in this phenomenon, the expression of the GluA1 subunit of the AMPA receptor and its phosphorylation states at serine residue 831 and 845 will be evaluated by total synaptosomes. Demonstrate that under the administration of intermittent ketogenic diet aged animals improve glucosa levels and long-term memory through the post-translational modifications such as phosphorylation at the serine 845 residue of GluA1 subunits of the AMPA receptor.