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Organization and regulation of paraventricular nucleus glutamate signaling systems: N-methyl-D-aspartate receptors

Authors

  • Dana R. Ziegler,

    Corresponding author
    1. Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45267-0559
    2. Graduate Program, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536
    • Dept. Psychological & Brain Sciences, Johns Hopkins University, 3400 N Charles St., Baltimore, MD 21218
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  • William E. Cullinan,

    1. Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53233
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  • James P. Herman

    1. Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45267-0559
    2. Graduate Program, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536
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Abstract

Stress activation of the hypothalamo–pituitary–adrenocortical (HPA) axis is mediated in part by glutamatergic neurotransmission. The precise nature of glutamate effects on stress-integrative hypothalamic paraventricular nucleus (PVN) neurons remains to be determined. Therefore, the current study was designed to delineate the organization of glutamate/NMDA receptor systems in the PVN and to assess regulation of PVN glutamate receptor subunit expression by chronic intermittent stress and glucocorticoids. Immunohistochemical studies verified that N-methyl-D-aspartate (NMDA) receptor subunit proteins NR1 and NR2A/2B are expressed in the medial parvocellular PVN, indicating the potential for NMDA receptor regulation of corticotropin-releasing hormone (CRH) release. Dual-label confocal analysis revealed that CRH neurons are apposed by vesicular glutamate transporter 2 (VGLUT2)-containing terminals, consistent with glutamatergic innervation from hypothalamus and/or brainstem. In situ hybridization analysis revealed a significant and selective stress-induced decrease (37%) in NR2B subunit mRNA expression in the CRH-containing region of the PVN. No changes were observed for NR1 or NR2A mRNAs. In contrast, none of the subunits investigated showed altered expression following adrenalectomy with or without low/high-dose corticosterone replacement. Thus, the observed stress regulation is likely mediated by neurogenic mechanisms in the PVN and upstream stress-transducing neurocircuitry. Because a loss of NR2B subunit inclusion in NR receptors would likely confer increased Ca++ conductance and faster deactivation kinetics, the stress-induced decrease in NR2B mRNA is consistent with enhanced glutamate signaling in the PVN following chronic stress and, perhaps, increased basal HPA activity and more rapid and/or more robust HPA responses to stress. J. Comp. Neurol. 484:43–56, 2005. © 2005 Wiley-Liss, Inc.

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