Prenatal kynurenine treatment in rats causes schizophrenia-like
broad monitoring deficits in adulthood
Carolyn H. Reneski
Received: 13 July 2017 /Accepted: 1 November 2017 /Published online: 11 November 2017
Springer-Verlag GmbH Germany, part of Springer Nature 2017
Rationale Elevated brain kynurenic acid (KYNA) levels are
implicated in the pathology and neurodevelopmental patho-
genesis of schizophrenia. In rats, embryonic treatment with
kynurenine (EKyn) causes elevated brain KYNA levels in
adulthood and cognitive deficits reminiscent of schizophrenia.
Objectives Growing evidence suggests that people with
schizophrenia have a narrowed attentional focus, and we
aimed at establishing whether these abnormalities may be re-
lated to KYNA dysregulation.
Methods To test whether EKyn rats display broad monitoring
deficits, kynurenine was added to the chow of pregnant Wistar
dams on embryonic days 15–22. As adults, 20 EKyn and 20
control rats were trained to stable performance on the five-
choice serial reaction time task, requiring the localization of
1-s light stimuli presented randomly across five apertures hor-
izontally arranged along a curved wall, equating the locomo-
tor demands of reaching each hole.
Results EKyn rats displayed elevated omission errors and re-
duced anticipatory responses relative to control rats, indicative
of a lower response rate, and showed reduced locomotor ac-
tivity. The ability to spread attention broadly was measured by
parsing performance by stimulus location. Both groups
displayed poorer stimulus detection with greater target loca-
tion eccentricity, but this effect was significantly more pro-
nounced in the EKyn group. Specifically, the groups differed
in the spatial distribution of correct but not incorrect
responses. This pattern cannot be explained by differences in
response rate and is indicative of a narrowed attentional focus.
Conclusions The findings suggest a potential etiology of
broad monitoring deficits in schizophrenia, which may con-
stitute a core cognitive deficit.
Keywords Kynurenic acid
5-Choice serial reaction time
Schizophrenia is marked not just by hallucinations, delusions,
and negative symptoms but also by a broad range of distinct
neurocognitive deficits that predict long-term functional dis-
ease outcome (Green 1996; Green et al. 2004). The pathogen-
esis of the symptoms of schizophrenia is increasingly thought
of as a convergence of neurodevelopmental risk factors,
namely the combination of genetic susceptibilities and envi-
ronmental perturbations during pre- and perinatal periods
(Fatemi and Folsom 2009; Lewis and Levitt 2002). In exper-
imental animals, several of these risk factors cause an increase
in the peripheral levels of kynurenine (Erhardt et al. 2017), a
major tryptophan metabolite, which readily crosses the blood-
brain barrier (Fukui et al. 1991). In the brain, kynurenine is
promptly converted to kynurenic acid (KYNA), an antagonist
of the glycine co-agonist site of the N-methyl-
glutamate receptor (NMDAR) and of the α7 nicotinic acetyl-
choline receptor (nAChR) (Hilmas et al. 2001; Kessler et al.
1989), or metabolized to other neuroactive metabolites includ-
ing 3-hydroxykynurenine and quinolinic acid (Schwarcz et al.
2012). Interestingly, KYNA levels have been consistently
shown to be elevated in cerebrospinal fluid and postmortem
brains of people with schizophrenia (PSZ) (Erhardt et al.
2001; Linderholm et al. 2012; Miller et al. 2006; Nilsson
* Britta Hahn
Maryland Psychiatric Research Center, University of Maryland
School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA
Psychopharmacology (2018) 235:651–661