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

• Published in: Psychopharmacology Vol. 233; no. 21-22; pp. 3725 - 3735
• Main Authors: Pershing, Michelle L., Phenis, David, Valentini, Valentina, Pocivavsek, Ana, Lindquist, Derick H., Schwarcz, Robert, Bruno, John P.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-10-2016; Springer; Springer Nature B.V
• Subjects: Age Factors; alpha7 Nicotinic Acetylcholine Receptor - drug effects; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animal cognition; Animals; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Brain - metabolism; Cognition; Cognition - drug effects; Conditioning, Psychological - drug effects; Fear; Female; Health aspects; Humans; Kynurenic Acid - metabolism; Kynurenine - pharmacology; Male; Metabolites; N-methyl-D-aspartate; Neurochemistry; Neurosciences; Original Investigation; Pharmacology/Toxicology; Pregnancy; Prenatal Exposure Delayed Effects; Psychiatry; Rats; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Schizophrenia; alpha7 nicotinic receptors; Methyl; aspartate receptors; Schizophrenia; Kynurenic acid; Prefrontal cortex; Trace fear conditioning; Glutamate; N-Methyl-D-aspartate receptors
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4404-9

Rationale
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.
Objectives
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.
Methods
Pregnant dams were fed unadulterated mash (progeny = ECON) or mash containing kynurenine (100 mg/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.
Results
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.
Conclusions
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.