Outcomes of Intrauterine Asphyxia in the Full Term Rat

Abstract

Intrauterine asphyxia, observed in 1-6 out of every 1,000 live full term births and nearly 60% of preterm births, is a component of many obstetric complications, including infection, preeclampsia, maternal diabetes, and intrauterine growth restriction. Numerous population-based studies show risk for developing schizophrenia is more than doubled following intrauterine asphyxia. The mechanistic link between intrauterine asphyxia and schizophrenia has yet to be elucidated. Intrauterine asphyxia causes an acute lack of oxygen in the blood, resulting in metabolic acidosis, hypercapnia, and hypoxia. Preclinical models have identified postnatal sequelae involving oxidative stress and inflammation, as well as alterations in the dopamine (DA) system that parallel abnormalities found in the schizophrenic brain. In particular, preclinical studies have identified an increased sensitivity to DA agonists, consistent with observed increases in DA activity in prodromal schizophrenic populations, suggesting a key DA system disturbance observed in the brain at the onset of schizophrenia can be induced by asphyxia at birth. How DA supersensitivity arises from birth asphyxia is unknown, but it is developmentally regulated, meaning that DA sensitivity may be preventable with early identification and intervention. However, there is no way to identify an individual that will develop DA supersensitivity prior to symptom onset. The aim of this experiment was to identify changes in the neurochemistry of forebrain dopamine targets usingin vivo magnetic resonance spectroscopy at ages prior to the emergence of DA supersensitivity. We observed developmental changes in the dorsal striatum (Str) and medial prefrontal cortex. In Str, the ratio of glutamine (Gln) to glutamate (Glu) measure on postnatal day (P) 7 was significantly increased in birth asphyxiated rats (APX) compared to non-asphyxiated (NON) littermates (p=.030), normalizing thereafter. On P35, APX show reduced Glu+Gln in the Str (p=.018) and increased Glu in the mPFC, relative to NON (p=.028). Str GABA was increased in APX at P7 (p=.023) and then decreased at P60 (p=.007) relative to NON. Further experiments are identifying in vitro dopamine metabolite and receptor levels in scanned brains