The Synthesis of GABA in Epileptic Brain

这个项目是项目1 （D. Coulter， PI）的“代谢对应物”，在项目1中，我们提供了证据表明

This project is the "metabolic counterpart" to Project 1 (D. Coulter, PI), where we present evidence that the Glutamate-Glutamine Cycle, ordinarily the major source for brain GABA synthesis, does not subserve this crucial role with a similar intensity in epileptic brain. We hypothesize that in epilepsy the brain recruits alternate precursors for the purpose of maintaining pools of GABA. In this project (M. Yudkoff, PI), we scrutinize this concept by using stable isotopes (primarily 15N and 13C) to identify major GABA precursors and to measure rates of GABA synthesis in the pilocarpine model of epilepsy. We will utilize mass spectrometry to quantify isotopic abundance. We have made productive use of this approach in our prior investigations of brain amino acid metabolism, and we seek now to apply the methodology to the study of epilepsy. Our preliminary findings confirm the concept that glutamine becomes a relatively less prominent GABA precursor in the pilocarpine model, particularly in the hippocampus. We find that alanine and leucine become two important donors of -NH2 groups to form the glutamate that the brain decarboxylates to yield GABA. We further hypothesize that the ketogenic diet, which we have previously demonstrated to increase brain GABA synthesis in non-epileptic animals, might have a similarly salutary effect in rats rendered epileptic by pilocarpine treatment. Indeed, a goal of this project will be to learn whether initiation of this diet prior to administration of pilocarpine might even attentuate or abort epileptogenesis.