Koranda JL, Ruskin DN, Masino SA, Blaise JH. A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats. Ketogenic diets are very low in carbohydrates and can reduce epileptic seizures significantly. This dietary therapy is particularly effective in pediatric and drugresistant epilepsy. Hypothesized anticonvulsant mechanisms of ketogenic diets focus on increased inhibition and/or decreased excitability/ excitation. Either of these consequences might not only reduce seizures, but also could affect normal brain function and synaptic plasticity. Here, we characterized effects of a ketogenic diet on hippocampal long-term potentiation, a widely studied form of synaptic plasticity. Adult male rats were placed on a control or ketogenic diet for 3 wk before recording. To maintain the most physiological conditions possible, we assessed synaptic transmission and plasticity using chronic in vivo recordings in freely behaving animals. Rats underwent stereotaxic surgery to chronically implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path; they recovered for 1 wk. After habituation and stable baseline recording, 5-Hz theta-burst stimulation was delivered to induce long-term potentiation. All animals showed successful plasticity, demonstrating that potentiation was not blocked by the ketogenic diet. Compared with rats fed a control diet, rats fed a ketogenic diet demonstrated significantly diminished long-term potentiation. This decreased potentiation lasted for at least 48 h. Reduced potentiation in ketogenic diet-fed rats is consistent with a general increase in neuronal inhibition (or decrease in excitability) and decreased seizure susceptibility. A better understanding of the effects of ketogenic diets on synaptic plasticity and learning is important, as diet-based therapy is often prescribed to children with epilepsy.
There is significant interest in in vivo synaptic plasticity in mice due to the many relevant genetic mutants now available. Nevertheless, use of in vivo models remains limited. To date long-term potentiation (LTP) has been studied infrequently, and long-term depression (LTD) has not been characterized in the mouse in vivo. Herein we describe protocols and improved methodologies we developed to record hippocampal synaptic plasticity reliably from the dentate gyrus of the awake freely behaving mouse. Seven days prior to recording, we implanted microelectrodes encapsulated within a lightweight, low profile head stage assembly. On the day of recording, we induced either LTP or LTD in the awake freely behaving animal, and monitored subsequent changes in population spike amplitude for at least 24h. Using this protocol we attained 80% success in inducing and maintaining either LTP or LTD. Recording from a chronic implant using this improved methodology is best suited to reveal naturally occurring brain activity and avoids both acute effects of local electrode insertion and drifts in neuronal excitability associated with anesthesia. Ultimately a reliable freely behaving mouse model of bi-directional synaptic plasticity is invaluable for full characterization of genetic models of disease states and manipulations of the mechanisms implicated in learning and memory.
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