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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS054900-04
Application #
8073038
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$251,488
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Trattnig, Sarah M; Gasiorek, Agnes; Deeb, Tarek Z et al. (2016) Copper and protons directly activate the zinc-activated channel. Biochem Pharmacol 103:109-17
Coulter, Douglas A; Steinhäuser, Christian (2015) Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med 5:a022434
Ah Mew, Nicholas; McCarter, Robert; Daikhin, Yevgeny et al. (2014) Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1 deficiency with N-carbamyl-L-glutamate. J Pediatr 165:401-403.e3
Abramian, Armen M; Comenencia-Ortiz, Eydith; Modgil, Amit et al. (2014) Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors. Proc Natl Acad Sci U S A 111:7132-7
Kahle, Kristopher T; Deeb, Tarek Z; Puskarjov, Martin et al. (2013) Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2. Trends Neurosci 36:726-737
Deeb, Tarek Z; Nakamura, Yasuko; Frost, Greg D et al. (2013) Disrupted Cl(-) homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states. Eur J Neurosci 38:2453-67
Deeb, Tarek Z; Maguire, Jamie; Moss, Stephen J (2012) Possible alterations in GABAA receptor signaling that underlie benzodiazepine-resistant seizures. Epilepsia 53 Suppl 9:79-88
Wang, Dian-Shi; Zurek, Agnieszka A; Lecker, Irene et al. (2012) Memory deficits induced by inflammation are regulated by ?5-subunit-containing GABAA receptors. Cell Rep 2:488-96
Hines, Rochelle M; Davies, Paul A; Moss, Stephen J et al. (2012) Functional regulation of GABAA receptors in nervous system pathologies. Curr Opin Neurobiol 22:552-8
Padgett, Claire L; Lalive, Arnaud L; Tan, Kelly R et al. (2012) Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA. Neuron 73:978-89

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