Abstracts

Rationale: Ketogenic (high fat, very low carbohydrate) diets (KD) can reduce epileptic seizures. Hypothesized anticonvulsant mechanisms of KD include (i) increased actions of inhibitory transmitters, modulators, and/or channels, and (ii) decreased excitability or levels of excitatory transmitters. Either of these consequences might not only reduce seizures but could also affect normal brain function and synaptic plasticity. Here, we characterize effects of a KD on adult hippocampal long-term potentiation (LTP), a widely-studied type of synaptic plasticity that is thought to be a potential cellular mechanism for learning and memory. To maintain the most normal physiological conditions possible we performed chronic in vivo recordings in freely behaving animals. Methods: Adult male Sprague-Dawley rats were placed on a control or KD (Bioserv #3666) for two weeks (ad libitum) prior to any manipulation. Under anesthesia, rats underwent stereotaxic surgery to chronically-implant electrodes in the dentate gyrus of the hippocampus (recording) and the perforant path (stimulating). After implantation, one week of post-surgical recovery was allowed before recording, resulting in a total of three weeks on a control or KD. Recordings took place in quiet chambers in which rats were habituated and allowed to move freely. Input/output (I/O) curves were obtained using the population spike amplitude of field potentials recorded in the dentate gyrus. Using the I/O curves, the 50% maximum current level was selected for subsequent stimulation. After 15 minutes of stable baseline, a tetanization pattern consisting of 5 Hz theta burst stimulation was delivered to induce LTP of the perforant path-dentate gyrus synapse. LTP was quantified as the post-tetanization % change in the population spike amplitude relative baseline levels. Intermittent recordings continued for 48 h after LTP induction. Results: Compared to adult male Sprague-Dawley rats fed a control diet, KD treatment for three weeks significantly diminished the magnitude of potentiation in the dentate gyrus. Decreased potentiation was recorded at almost all time points, including the first time point tested (1 min) and up to and including the last time point (48 h after LTP induction). No overt behavioral differences were observed. Conclusions: Three weeks on a KD reduces the magnitude of LTP in the dentate gyrus of freely behaving adult rats. These initial results are contrary to recent published work showing no effect of a KD on LTP in vivo. Methodological differences could account for this discrepancy, and are important to resolve. Reduced potentiation in rats fed a KD is consistent with a general increase in inhibition (or decrease in excitation) and an increase in seizure threshold. It is important to determine whether the reduced LTP reported here in adult animals is also present in juveniles, as a KD is often prescribed to children with epilepsy. In addition, it is important to determine if a KD impacts normal learning and memory significantly, and if these effects are reversible (and within what time frame) upon return to a control diet.