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Post-Pubertal Disruption of Medial Prefrontal Cortical Dopamine–Glutamate Interactions in a Developmental Animal Model of Schizophrenia

  • Kuei-Yuan Tseng
    Affiliations
    Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, New York

    Department of Cellular & Molecular Pharmacology, Chicago Medical School/Rosalind Franklin University of Medicine & Science, North Chicago, Illinois
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  • Barbara L. Lewis
    Affiliations
    Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, New York
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  • Barbara K. Lipska
    Affiliations
    Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda
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  • Patricio O’Donnell
    Correspondence
    Address reprint requests to Patricio O’Donnell, M.D., Ph.D., University of Maryland School of Medicine, Department of Anatomy & Neurobiology, 20 Penn St., Baltimore, MD 21201.
    Affiliations
    Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, New York

    Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland
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      Background

      A neonatal ventral hippocampal lesion (NVHL) induces behavioral and physiological anomalies mimicking pathophysiological changes of schizophrenia. Because prefrontal cortical (PFC) pyramidal neurons recorded from adult NVHL rats exhibit abnormal responses to activation of the mesocortical dopaminergic (DA) system, we explored whether these changes are due to an altered DA modulation of pyramidal neurons.

      Methods

      Whole-cell recordings were used to examine the effects of DA and glutamate agonists on cell excitability in brain slices obtained from pre- (postnatal day [PD] 28–35) and post-pubertal (PD > 61) sham and NVHL animals.

      Results

      N-methyl d-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole propionate (AMPA), and the D1 agonist SKF38393 increased excitability of deep layer pyramidal neurons in a concentration-dependent manner. The opposite effect was observed with the D2 agonist quinpirole. The effects of NMDA (but not AMPA) and SKF38393 on cell excitability were significantly higher in slices from NVHL animals, whereas quinpirole decrease of cell excitability was reduced. These differences were not observed in slices from pre-pubertal rats, suggesting that PFC DA and glutamatergic systems become altered after puberty in NVHL rats.

      Conclusions

      A disruption of PFC dopamine–glutamate interactions might emerge after puberty in brains with an early postnatal deficit in hippocampal inputs, and this disruption could contribute to the manifestation of schizophrenia-like symptoms.

      Key Words

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