Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior.
Neuropsychopharmacology
; 35(8): 1734-42, 2010 Jul.
Article
em En
| MEDLINE
| ID: mdl-20336058
ABSTRACT
At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the alpha 7 nicotinic acetylcholine receptor and, possibly, the glycine co-agonist site of the NMDA receptor. The functions of these two receptors, which are intimately involved in synaptic plasticity and cognitive processes, may, therefore, be enhanced by reductions in brain KYNA levels. This concept was tested in mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. At 21 days of age, KAT II knock-out mice had reduced hippocampal KYNA levels (-71%) and showed significantly increased performance in three cognitive paradigms that rely in part on the integrity of hippocampal function, namely object exploration and recognition, passive avoidance, and spatial discrimination. Moreover, compared with wild-type controls, hippocampal slices from KAT II-deficient mice showed a significant increase in the amplitude of long-term potentiation in vitro. These functional changes were accompanied by reduced extracellular KYNA (-66%) and increased extracellular glutamate (+51%) concentrations, measured by hippocampal microdialysis in vivo. Taken together, a picture emerges in which a reduction in the astrocytic formation of KYNA increases glutamatergic tone in the hippocampus and enhances cognitive abilities and synaptic plasticity. Our studies raise the prospect that interventions aimed specifically at reducing KYNA formation in the brain may constitute a promising molecular strategy for cognitive improvement in health and disease.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cognição
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Potenciação de Longa Duração
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Ácido Glutâmico
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Hipocampo
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Ácido Cinurênico
Limite:
Animals
Idioma:
En
Revista:
Neuropsychopharmacology
Assunto da revista:
NEUROLOGIA
/
PSICOFARMACOLOGIA
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos