The experiments proposed in this application are intended to study the role of the kynurenine pathway in mammalian brain. This pathway of tryptophan metabolism produces the excitotoxic neurotoxins, 3- hydroxykynurenine (3 -HK) and quinolinic acid (QUIN) and the neuroprotectant, kynurenic acid (KYNA). Abnormalities in this pathway have been identified in brains of patients with Huntington's Disease, Alzheimer's Disease and Schizophrenia. However, the neurobiological significance of this pathway is poorly understood. Given the ability of these metabolites (""""""""kynurenines"""""""") to affect glutamate receptors, the proposed experiments will assess their putative role as modulators of glutamatergic neurotransmission during development. Using a mouse that is nullizygous for a major KYNA producing enzyme, kynurenine aminotransferase B (KAT II), we shall examine CNS development in the absence of an endogenous glutamate receptor antagonist. Specifically, we will characterize the kynurenine pathway of wild-type 129 SvEv mice and KAT B knockout mice during development. In order to assess the functional consequences of this genetic lesion, we will examine morphological differences in KAT II knockout mice, assess whether these mice display altered performance on tests of memory and determine if they show increased sensitivity to excitotoxins .

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS042487-03
Application #
6659841
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (20))
Program Officer
Oliver, Eugene J
Project Start
2002-09-30
Project End
Budget Start
2003-09-30
Budget End
2004-09-29
Support Year
3
Fiscal Year
2003
Total Cost
$5,911
Indirect Cost
Name
University of Maryland Baltimore
Department
Psychiatry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Guidetti, Paolo; Amori, Laura; Sapko, Michael T et al. (2007) Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J Neurochem 102:103-11
Sapko, Michael T; Guidetti, Paolo; Yu, Ping et al. (2006) Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: Implications for Huntington's disease. Exp Neurol 197:31-40