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Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats

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Abstract

Rationale

Cognitive dysfunctions, including deficits in hippocampus-mediated learning and memory, are core features of the psychopathology of schizophrenia (SZ). Increased levels of kynurenic acid (KYNA), an astrocyte-derived tryptophan metabolite and antagonist of α7 nicotinic acetylcholine and N-methyl-d-aspartate receptors, have been implicated in these cognitive impairments.

Objectives

Following recent suggestive evidence, the present study was designed to narrow the critical time period for KYNA elevation to induce subsequent cognitive deficits.

Methods

KYNA levels were experimentally increased in rats (1) prenatally (embryonic day (ED) 15 to ED 22) or (2) during adolescence (postnatal day (PD) 42 to PD 49). The KYNA precursor kynurenine was added daily to wet mash fed to (1) dams (100 mg/day; control: ECon; kynurenine-treated: EKyn) or (2) adolescent rats (300 mg/kg/day; control: AdCon; kynurenine-treated: AdKyn). Upon termination of the treatment, all animals were fed normal chow until biochemical analysis and behavioral testing in adulthood.

Results

On the last day of continuous kynurenine treatment, forebrain KYNA levels were significantly elevated (EKyn +472 %; AdKyn +470 %). KYNA levels remained increased in the hippocampus of adult EKyn animals (+54 %), but were unchanged in adult AdKyn rats. Prenatal, but not adolescent, kynurenine treatment caused significant impairments in two hippocampus-mediated behavioral tasks, passive avoidance and Morris water maze.

Conclusions

Collectively, these studies provide evidence that a continuous increase in brain KYNA levels during the late prenatal period, but not during adolescence, induces hippocampus-related cognitive dysfunctions later in life. Such increases may play a significant role in illnesses with known hippocampal pathophysiology, including SZ.

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Acknowledgments

This work was supported by USPHS grant MH83729 to JPB and RS.

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Authors and Affiliations

  1. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD, 21228, USA

    Ana Pocivavsek, Marian A. R. Thomas, Greg I. Elmer & Robert Schwarcz

  2. Departments of Psychology and Neuroscience, The Ohio State University, Columbus, OH, USA

    John P. Bruno

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  1. Ana Pocivavsek
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  2. Marian A. R. Thomas
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  3. Greg I. Elmer
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  4. John P. Bruno
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  5. Robert Schwarcz
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Correspondence to Robert Schwarcz.

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Pocivavsek, A., Thomas, M.A.R., Elmer, G.I. et al. Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats. Psychopharmacology 231, 2799–2809 (2014). https://doi.org/10.1007/s00213-014-3452-2

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