Prenatal kynurenine exposure in rats: age-dependent changes in NMDA receptor expression and conditioned fear responding.

Abstract

Levels of kynurenic acid (KYNA), an endogenous negative modulator of alpha 7 nicotinic acetylcholine receptors (α7nAChRs) and antagonist at glutamatergic N-methyl-D-aspartate receptors (NMDARs), are elevated in the brain of patients with schizophrenia (SZ). In rats, dietary exposure to KYNA's immediate precursor kynurenine during the last week of gestation produces neurochemical and cognitive deficits in adulthood that resemble those seen in patients with SZ. The present experiments examined whether prenatal kynurenine exposure results in age-dependent changes in the kynurenine pathway (KP), expression of selected receptors, and cognitive function. Pregnant dams were fed unadulterated mash (progeny=ECON) or mash containing kynurenine (100mg/day; progeny=EKYN) from embryonic day (ED) 15 to 22. Male offspring were assessed as juveniles, i.e., prior to puberty (postnatal day [PD] 32), or as adults (PD70) for brain KYNA levels, α7nAChR and NMDAR gene expression, and performance on a trace fear conditioning (TFC) task. KYNA levels were comparable between juvenile ECON and EKYN rats, whereas EKYN adults exhibited a ~3-fold increase in brain KYNA relative to ECONs. NR2A expression was persistently reduced (30-40%) in EKYN rats at both ages. Compared to ECON adults, there was a 50% reduction in NR1, and a trend toward decreased α7nAChR expression, in adult EKYN rats. Surprisingly, juvenile EKYN rats performed significantly better in the TFC paradigm than controls, whereas adult EKYN animals showed the predicted deficits. Collectively, our results provide evidence that KP changes in the fetal brain alter neuronal development and cause age-dependent effects on neurochemistry and cognitive performance.