Abstracts

The mechanisms underlying the efficacy of the ketogenic diet are unclear, but it has been hypothesized that the metabolism of ketones, including betahydroxybutyrate, is a critical aspect of the therapy. BHB can replace glucose to support synaptic functioning in young rats, but not adults. Here we have examined the effects of BHB on synaptic transmission in mildly hypoglycemic conditions to test the hypothesis that BHB can partially restore synaptic transmission in adult animals during periods of metabolic demand.
Hippocampal slices were prepared from adult Sprague-Dawley rats and maintained in an interface recording chamber. Field potential recordings were made in the cell body layer of both the CA1 and the dentate gyrus. Input-output curves and the responses to 5 and 10 Hz repetitive orthodromic stimulation (10 sec trains) were obtained under three different recording conditions: control ACSF (10 mM glucose); ACSF containing 2 mM glucose made iso-osmotic with sucrose and ACSF containing 2 mM glucose and 8 mM BHB. The data were normalized to the peak response recorded in control medium.
Bath application of low glucose (2 mM from 10 mM) was associated with a slight decrease in the amplitude of the population spikes (PS) and in the PS slope in both the CA1 and DG, n=6. The slope, but not the amplitude of the CA1 PS partially recovered following bath application of BHB in CA1, but not in the dentate. When we examined the responses elicited by repetitive stimulation in low glucose, we found that there was a depression of the synaptic response (population spike amplitude) during the train in 2 mM glucose as compared to 10 mM in both CA1 and the dentate. When BHB was present, this depression was reduced and approached the levels seen in control ACSF. This effect of BHB was seen in both CA1 and in the DG, but was more significant for the CA1 region. In contrast, this effect was not seen when acetate, a substrate for the glial moncarboxylic acid transporter, was added to the ACSF, n=2.
In hypoglycemic conditions, we found that BHB, but not acetate, is able to substitute for glucose in both the CA1 and dentate gyrus under specific conditions. This effect is stronger in the CA1 than in the dentate gyrus, suggesting that there are regional differences in the ability of neurons in these areas either to take up BHB through the neuronal monocarboxylic acid transporter or in the ability of these cells to metabolize BHB. The BHB effect is primarily seen when the tissue is metabolically stressed, suggesting that BHB can be metabolized by adult neurons, but that glucose metabolism needs to be impaired. Taken together, these data indicate that improving neuronal, as compared to glial, metabolism in normal tissue exposed to mild hypoglycemia is critical to supporting synaptic function. These data may be useful for understanding the efficacy of the ketogenic diet.
[Supported by: NIH grant PO1NS39092]