title: 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 (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.
  
  
  
  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.
authors.affiliation: Department of Psychology, The Ohio State University, Columbus, OH, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Pershing
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
authors.forename: David
authors.initials: D
authors.lastname: Phenis
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Valentini
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Pocivavsek
authors.affiliation: Department of Psychology, The Ohio State University, Columbus, OH, USA.|Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
authors.forename: Derick H
authors.initials: DH
authors.lastname: Lindquist
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.affiliation: Department of Psychology, The Ohio State University, Columbus, OH, USA. bruno.1@osu.edu.|Department of Neuroscience, The Ohio State University, Columbus, OH, USA. bruno.1@osu.edu.
authors.forename: John P
authors.initials: JP
authors.lastname: Bruno
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D005239:Fear; D005260:Female; D006801:Humans; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000494:pharmacology*; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D012559:Schizophrenia; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007736:Kynurenic Acid; D007737:Kynurenine; D016194:Receptors, N-Methyl-D-Aspartate; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579165:Chrna7 protein, rat; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor
keywords: Glutamate; Kynurenic acid; N-Methyl-D-aspartate receptors; Prefrontal cortex; Schizophrenia; Trace fear conditioning; alpha7 nicotinic receptors