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 .
| 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 |
