Excitatory amino acids (EAAs) and their receptors play an important role in brain development. It follows that impaired EAA function during the perinatal period will have grave consequences, possibly including mental retardation. Kynurenic acid (KYNA), a metabolite of tryptophan, is present in the brain under physiological conditions and can function as an antagonist of EAA receptors. At endogenous brain concentrations, KYNA also blocks the alpha7 nicotinic acetylcholine receptor, which is involved in synaptogenesis and cognitive processes. Brain KYNA levels are remarkably high during gestation and fall precipitously immediately after birth. This fact, the tight regulation of KYNA formation in the brain, and the ability of KYNA to protect against the effects of perinatal hypoxia, have given rise to the hypothesis that KYNA is an important neuromodulator during the perinatal period. KYNA dysfunction in the immature brain may therefore have harmful effects on the developing brain and beyond. This project will examine the possible role of KYNA in two pathological conditions known to afflict the developing human brain, i.e. prenatal hypoxia and childhood hypoglycemia, the latter a by-product of insulin treatment in juvenile diabetes. In animals, both hypoxic and hypoglycemic episodes cause structural and cognitive changes in the brain due to overactive glutamatergic function (excitotoxicity). Since these insults also interfere with cerebral KYNA synthesis, pharmacological up-regulation of brain KYNA levels may prove beneficial to the injured developing brain. During the coming grant period, kynurenine aminotransferases (KATs) II and III- the two major synthetic enzymes of brain KYNA - will be studied at different stages of development, and their relative importance in the control of brain KYNA will be assessed in mouse models of prenatal hypoxia or early postnatal hypoglycemia. Pharmacological interventions known to increase or reduce brain KYNA will then be used to improve or worsen, respectively, brain abnormalities caused by these early insults. These studies will be extended to include mice genetically engineered to lack KAT II. Taken together, these studies will comprehensively elaborate the role of an endogenous neuromodulator, KYNA, in the pathophysiology of two clinically relevant models of perinatal hypoxia and hypoglycemia. In addition, the planned studies will explore novel molecular mechanisms that specifically influence brain KYNA levels and thus may affect the acute and chronic consequences of these developmental insults.
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