Regulation of Kainate Receptor Subunit mRNA by Stress and Corticosteroids in the Rat Hippocampus Richard G. Hunter*, Rudy Bellani, Erik Bloss, Ana Costa, Katharine McCarthy, Bruce S. McEwen Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York, United States of America Abstract Kainate receptors are a class of ionotropic glutamate receptors that have a role in the modulation of glutamate release and synaptic plasticity in the hippocampal formation. Previous studies have implicated corticosteroids in the regulation of these receptors and recent clinical work has shown that polymorphisms in kainate receptor subunit genes are associated with susceptibility to major depression and response to anti-depressant treatment. In the present study we sought to examine the effects of chronic stress and corticosteroid treatments upon the expression of the mRNA of kainate receptor subunits GluR5-7 and KA1-2. Our results show that, after 7 days, adrenalectomy results in increased expression of hippocampal KA1, GluR6 and GluR7 mRNAs, an effect which is reversed by treatment with corticosterone in the case of KA1 and GluR7 and by aldosterone treatment in the case of GluR6. 21 days of chronic restraint stress (CRS) elevated the expression of the KA1 subunit, but had no effect on the expression of the other subunits. Similarly, 21 days of treatment with a moderate dose of corticosterone also increased KA1 mRNA in the dentate gyrus, whereas a high corticosterone dose has no effect. Our results suggest an interaction between hippocampal kainate receptor composition and the hypothalamic-pituitary-adrenal (HPA) axis and show a selective chronic stress induced modulation of the KA1 subunit in the dentate gyrus and CA3 that has implications for stress-induced adaptive structural plasticity. Citation: Hunter RG, Bellani R, Bloss E, Costa A, McCarthy K, et al. (2009) Regulation of Kainate Receptor Subunit mRNA by Stress and Corticosteroids in the Rat Hippocampus. PLoS ONE 4(1): e4328. doi:10.1371/journal.pone.0004328 Editor: Bernhard Baune, James Cook University, Australia Received September 11, 2008; Accepted October 31, 2008; Published January 30, 2009 Copyright: 2009 Hunter et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by NIH MH 15125, MH41256 and MH065749. RGH was supported by the Gary R. Helman Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: rhunter@rockefeller.edu Introduction The hippocampal formation, due to its high levels of expression of receptors for corticosteroid stress hormones, is particularly suscep- tible to weathering and structural changes as a result of chronic stress and stress related diseases such as depression. The interplay of corticosteroids and ionotropic excitatory amino acid receptors in producing structural and physiologic changes in the hippocampal formation has been the subject of a significant amount of research, but most of this research has focused upon NMDA and AMPA receptors while relatively little has sought to describe the effects of corticosteroids upon the expression of kainate receptors (KAR). There are five members to the KAR gene family: GluR5, 6 and 7 and KA 1 and 2 [1] and kainate receptors are comprised of various admixtures of the five subunit proteins produced by these genes. The KARs contribute to both excitatory neurotransmission and the presynaptic modulation of neurotransmitter release [2–4]. Notably, KAR activation contributes to LTP in the hippocampus, particularly at the mossy fiber synapse of the CA3 [5]. A number of recent clinical studies have shown KARs have potentially important roles in a number of major mental disorders, particularly depression. Polymorphisms in the KA1 receptor have been associated with response to the anti-depressant citalopram and GluR6 has been associated with suicidal ideation during treatment with the same drug [6,7]. The GluR7 gene has also been connected to recurrent major depression [8]. KA1, GluR5 and GluR6 have also shown association with schizophrenia and bipolar disorder [9,10]. The first study to examine the effects of corticosteroids upon hippocampal KAR was performed by Clark and Cotman [11], who tested the effects of adrenalectomy and corticosterone (CORT) replacement on binding at AMPAR, KAR and NMDAR and found no replicable effect of corticosterone or adrenalectomy on 3H kainate binding. Watanabe [12], did however, observe a decrease in 3H kainate binding after adrenalectomy, an effect which was blocked by replacement with the selective mineralocorticoid receptor (MR) agonist aldosterone but not the glucocorticoid receptor (GR) selective agonist RU28362. A study examining the expression of mRNA for KAR subunits 3 days after adrenalectomy and in response to acute high and low dose CORT showed that low doses of CORT, which presumptively occupy only MR, increased expression of all subunits, while ADX or high dose CORT (occupying both MR and GR) failed to significantly alter expression of any subunit [13]. Finally, chronic peripheral administration of the GR agonist dexamethasone increases expression of GluR6 protein in the dentate gyrus and CA3 [14]. To date these studies constitute most of what is known about the interactions of corticosteroids and the KAR. The present study aims to add to our understanding of these interactions by examining the extent to which different kainate receptor subunit mRNA’s are regulated differentially by stress and adrenal steroids, using adrenalectomy, hormone replace- ment, chronic restraint stress and chronic corticosterone treatment of adrenally intact animals. PLoS ONE | www.plosone.org 1 January 2009 | Volume 4 | Issue 1 | e4328