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Downregulation of Ccnd1 and Hes6 in rat hippocampus after chronic exposure to the antidepressant paroxetine

Published online by Cambridge University Press:  24 June 2014

Patrick C. McHugh ,
Geraldine R. Rogers ,
Dylan M. Glubb ,
Melanie D. Allington ,
Mark Hughes ,
Peter R. Joyce  and
Martin A. Kennedy
Patrick C. McHugh
Affiliation:
Department of Pathology, University of Otago, Christchurch, Christchurch, New Zealand
Geraldine R. Rogers
Affiliation:
Department of Pathology, University of Otago, Christchurch, Christchurch, New Zealand
Dylan M. Glubb
Affiliation:
Department of Pathology, University of Otago, Christchurch, Christchurch, New Zealand
Melanie D. Allington
Affiliation:
Department of Pathology, University of Otago, Christchurch, Christchurch, New Zealand
Mark Hughes
Affiliation:
Genetics Factors, Riccarton, Christchurch, New Zealand
Peter R. Joyce
Affiliation:
Department of Psychological Medicine, University of Otago, Christchurch, Christchurch, New Zealand
Martin A. Kennedy*
Affiliation:
Department of Pathology, University of Otago, Christchurch, Christchurch, New Zealand
*
Associate Professor Martin A. Kennedy, Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch 8011, New Zealand. Tel: (64-3) 364-1222; Fax: (64-3) 364-0009; E-mail: martin.kennedy@otago.ac.nz
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Abstract

Objective:

The mechanism of action of antidepressant drugs is not fully understood. Application of genomic methods enables the identification of biochemical pathways that are regulated by antidepressants, and this may provide novel clues to the molecular and cellular actions of these drugs. The present study examined gene expression profiles in the hippocampus of rats exposed to chronic antidepressant treatment.

Methods:

Animals were treated for 12 days with the selective serotonin reuptake inhibitor paroxetine; then, hippocampal ribonucleic acid was recovered, and changes in gene expression were assessed by microarray analysis.

Results:

A total of 160 genes that showed differential expression after paroxetine exposure were identified. Using functional relevance and observed fold change as selection criteria, the expression changes in a subset of these genes were confirmed by quantitative polymerase chain reaction.

Conclusion:

Of this subset, only two genes, cyclin D1 (Ccnd1) and hairy and enhancer of split 6 (Hes6), showed robust and consistent changes in expression. Both genes were downregulated by paroxetine, and both have been previously implicated in neurogenesis. Further investigation of these two genes may provide new insight into the mechanism of action of antidepressants.

Keywords

microarrayneurogenesispharmacogenomicsparoxetineselective serotonin reuptake inhibitorSTAT3
Type
Research Article
Information
Acta Neuropsychiatrica , Volume 20 , Issue 6 , December 2008 , pp. 307 - 313
Copyright
Copyright © 2008 Blackwell Munksgaard

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References

Elhwuegi, AS. Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:435–451. CrossRefGoogle ScholarPubMed
Ressler, KJ, Nemeroff, CB. Role of norepinephrine in the pathophysiology and treatment of mood disorders. Biol Psychiatry 1999;46:1219–1233. CrossRefGoogle ScholarPubMed
Nestler, EJ. Antidepressant treatments in the 21st century. Biol Psychiatry 1998;44:526–533. CrossRefGoogle ScholarPubMed
Dubovsky, SL. Beyond the serotonin reuptake inhibitors: rationales for the development of new serotonergic agents. J Clin Psychiatry 1994;55(Suppl.):34–44. Google ScholarPubMed
Malberg, JE, Blendy, JA. Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci 2005;26:631–638. CrossRefGoogle ScholarPubMed
Malberg, JE, Duman, RS. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 2003;28:1562–1571. CrossRefGoogle ScholarPubMed
McEwen, BS. Stress and hippocampal plasticity. Annu Rev Neurosci 1999;22:105–122. CrossRefGoogle ScholarPubMed
Schiepers, OJ, Wichers, MC, Maes, M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:201–217. CrossRefGoogle ScholarPubMed
Zorrilla, EP, Valdez, GR, Weiss, F. Changes in levels of regional CRF-like-immunoreactivity and plasma corticosterone during protracted drug withdrawal in dependent rats. Psychopharmacology (Berl) 2001;158:374–381. CrossRefGoogle ScholarPubMed
Czeh, B, Lucassen, PJ. What causes the hippocampal volume decrease in depression?: Are neurogenesis, glial changes and apoptosis implicated? Eur Arch Psychiatry Clin Neurosci 2007;257:250–260. Google Scholar
Young, EA, Haskett, RF, Murphy-Weinberg, V, Watson, SJ, Akil, H. Loss of glucocorticoid fast feedback in depression. Arch Gen Psychiatry 1991;48:693–699. CrossRefGoogle ScholarPubMed
Kaestner, F, Hettich, M, Peters, Met al. Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity. J Affect Disord 2005;87:305–311. CrossRefGoogle ScholarPubMed
Gur, TL, Conti, AC, Holden, Jet al. cAMP response element-binding protein deficiency allows for increased neurogenesis and a rapid onset of antidepressant response. J Neurosci 2007;27:7860–7868. CrossRefGoogle Scholar
Santarelli, L, Saxe, M, Gross, Cet al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003;301:805–809. CrossRefGoogle ScholarPubMed
Brazma, A, Hingamp, P, Quackenbush, Jet al. Minimum information about a microarray experiment (MIAME) – toward standards for microarray data. Nat Genet 2001;29:365–371. CrossRefGoogle ScholarPubMed
DeVane, CL. Metabolism and pharmacokinetics of selective serotonin reuptake inhibitors. Cell Mol Neurobiol 1999;19:443–466. CrossRefGoogle ScholarPubMed
Yang, IV, Chen, E, Hasseman, JPet al. Within the fold: assessing differential expression measures and reproducibility in microarray assays. Genome Biol 2002;3:research0062. Google ScholarPubMed
Rajeevan, MS, Vernon, SD, Taysavang, N, Unger, ER. Validation of array-based gene expression profiles by real-time (kinetic) RT-PCR. J Mol Diagn 2001;3:26–31. CrossRefGoogle ScholarPubMed
Wang, Y, Barbacioru, C, Hyland, Fet al. Large scale real-time PCR validation on gene expression measurements from two commercial long-oligonucleotide microarrays. BMC Genomics 2006;7:59. CrossRefGoogle ScholarPubMed
Jurata, LW, Bukhman, YV, Charles, Vet al. Comparison of microarray-based mRNA profiling technologies for identification of psychiatric disease and drug signatures. J Neurosci Methods 2004;138:173–188. CrossRefGoogle ScholarPubMed
Wurmbach, E, Gonzalez-Maeso, J, Yuen, Tet al. Validated genomic approach to study differentially expressed genes in complex tissues. Neurochem Res 2002;27:1027–1033. CrossRefGoogle ScholarPubMed
Sherr, CJ, Roberts, JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501–1512. CrossRefGoogle ScholarPubMed
Fu, M, Wang, C, Li, Z, Sakamaki, T, Pestell, RG. Minireview: cyclin D1: normal and abnormal functions. Endocrinology 2004;145:5439–5447. CrossRefGoogle ScholarPubMed
Bienvenu, F, Gascan, H, Coqueret, O. Cyclin D1 represses STAT3 activation through a Cdk4-independent mechanism. J Biol Chem 2001;276:16840–16847. CrossRefGoogle ScholarPubMed
Gertsch, J, Guttinger, M, Sticher, O, Heilmann, J. Relative quantification of mRNA levels in Jurkat T cells with RT-real time-PCR (RT-rt-PCR): new possibilities for the screening of anti-inflammatory and cytotoxic compounds. Pharm Res 2002;19:1236–1243. CrossRefGoogle Scholar
Landgrebe, J, Welzl, G, Metz, Tet al. Molecular characterisation of antidepressant effects in the mouse brain using gene expression profiling. J Psychiatr Res 2002;36:119–129. CrossRefGoogle ScholarPubMed
Drigues, N, Poltyrev, T, Bejar, C, Weinstock, M, Youdim, MB. cDNA gene expression profile of rat hippocampus after chronic treatment with antidepressant drugs. J Neural Transm 2003;110:1413–1436. CrossRefGoogle ScholarPubMed
Chen, J, Zhang, Y, Kelz, MBet al. Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of [Delta]FosB. J Neurosci 2000;20:8965–8971. Google Scholar
Newton, SS, Collier, EF, Hunsberger, Jet al. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J Neurosci 2003;23:10841–10851. Google ScholarPubMed
Koyano-Nakagawa, N, Kim, J, Anderson, D, Kintner, C. Hes6 acts in a positive feedback loop with the neurogenins to promote neuronal differentiation. Development 2000;127:4203–4216. Google Scholar
Bae, S, Bessho, Y, Hojo, M, Kageyama, R. The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation. Development 2000;127:2933–2943. Google ScholarPubMed
Kageyama, R, Ishibashi, M, Takebayashi, K, Tomita, K. bHLH transcription factors and mammalian neuronal differentiation. Int J Biochem Cell Biol 1997;29:1389–1399. CrossRefGoogle ScholarPubMed
Altar, CA, Laeng, P, Jurata, LWet al. Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways. J Neurosci 2004;24:2667–2677. CrossRefGoogle ScholarPubMed
Kamakura, S, Oishi, K, Yoshimatsu, T, Nakafuku, M, Masuyama, N, Gotoh, Y. Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol 2004;6:547–554. CrossRefGoogle ScholarPubMed
Wong, ML, O’Kirwan, F, Hannestad, JP, Irizarry, KJ, Elashoff, D, Licinio, J. St John’s wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response. Mol Psychiatry 2004;9:237–251. CrossRefGoogle ScholarPubMed
Conti, B, Maier, R, Barr, AMet al. Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine. Mol Psychiatry 2006;12:167–189. CrossRefGoogle ScholarPubMed
Fior, R, Henrique, D. A novel hes5/hes6 circuitry of negative regulation controls Notch activity during neurogenesis. Dev Biol 2005;281:318–333. CrossRefGoogle ScholarPubMed
Chen, B, Wang, JF, Sun, X, Young, LT. Regulation of GAP-43 expression by chronic desipramine treatment in rat cultured hippocampal cells. Biol Psychiatry 2003;53:530–537. CrossRefGoogle ScholarPubMed
Palotas, M, Palotas, A, Puskas, LGet al. Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram. Int J Neuropsychopharmacol 2004;7:401–413. CrossRefGoogle ScholarPubMed
Yamada, M, Takahashi, K, Tsunoda, Met al. Differential expression of VAMP2/synaptobrevin-2 after antidepressant and electroconvulsive treatment in rat frontal cortex. Pharmacogenomics J 2002;2:377–382. CrossRefGoogle ScholarPubMed
Yamada, M, Yamazaki, S, Takahashi, Ket al. Induction of cysteine string protein after chronic antidepressant treatment in rat frontal cortex. Neurosci Lett 2001;301:183–186. CrossRefGoogle ScholarPubMed
Yamada, M, Yamazaki, S, Takahashi, Ket al. Identification of a novel gene with RING-H2 finger motif induced after chronic antidepressant treatment in rat brain. Biochem Biophys Res Commun 2000;278:150–157. CrossRefGoogle ScholarPubMed
Huang, NY, Strakhova, M, Layer, RT, Skolnick, P. Chronic antidepressant treatments increase cytochrome b mRNA levels in mouse cerebral cortex. J Mol Neurosci 1997;9:167–176. CrossRefGoogle ScholarPubMed
Wong, ML, Khatri, P, Licinio, J, Esposito, A, Gold, PW. Identification of hypothalamic transcripts upregulated by antidepressants. Biochem Biophys Res Commun 1996;229:275–279. CrossRefGoogle ScholarPubMed
Yamada, M, Kiuchi, Y, Nara, Ket al. Identification of a novel splice variant of heat shock cognate protein 70 after chronic antidepressant treatment in rat frontal cortex. Biochem Biophys Res Commun 1999;261:541–545. CrossRefGoogle ScholarPubMed
Chen, J, Newton, SS, Zeng, Let al. Downregulation of the CCAAT-enhancer binding protein beta in deltaFosB transgenic mice and by electroconvulsive seizures. Neuropsychopharmacology 2004;29:23–31. Google Scholar
Rausch, JL, Gillespie, CF, Fei, Yet al. Antidepressant effects on kinase gene expression patterns in rat brain. Neurosci Lett 2002;334:91–94. CrossRefGoogle ScholarPubMed
Kothapalli, R, Yoder, SJ, Mane, S, Loughran, TP Jr. Microarray results: how accurate are they? BMC Bioinformatics 2002;3:22. CrossRefGoogle Scholar
Chuaqui, RF, Bonner, RF, Best, CJet al. Post-analysis follow-up and validation of microarray experiments. Nat Genet 2002;32(Suppl.):509–514. CrossRefGoogle ScholarPubMed
Duman, CH, Schlesinger, L, Kodama, M, Russell, DS, Duman, RS. A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol Psychiatry 2007;61:661–670. CrossRefGoogle ScholarPubMed
Nakagawa, S, Kim, JE, Lee, Ret al. Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J Neurosci 2002;22:3673–3682. Google ScholarPubMed
Fujioka, T, Fujioka, A, Duman, RS. Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus. J Neurosci 2004;24:319–328. CrossRefGoogle ScholarPubMed
Celano, E, Tiraboschi, E, Consogno, Eet al. Selective regulation of presynaptic calcium/calmodulin-dependent protein kinase II by psychotropic drugs. Biol Psychiatry 2003;53:442–449. CrossRefGoogle ScholarPubMed
McHugh, PC, Rogers, GR, Loudon, B, Glubb, DM, Joyce, PR, Kennedy, MA. Proteomic analysis of embryonic stem cell-derived neural cells exposed to the antidepressant paroxetine. J Neurosci Res 2008;86:306–316. CrossRefGoogle ScholarPubMed
Guo, GG, Patel, K, Kumar, Vet al. Association of the chaperone glucose-regulated protein 58 (GRP58/ER-60/ERp57) with Stat3 in cytosol and plasma membrane complexes. J Interferon Cytokine Res 2002;22:555–563. CrossRefGoogle ScholarPubMed
Sehgal, PB. Plasma membrane rafts and chaperones in cytokine/STAT signaling. Acta Biochim Pol 2003;50:583–594. Google ScholarPubMed
Fricker, AD, Rios, C, Devi, LA, Gomes, I. Serotonin receptor activation leads to neurite outgrowth and neuronal survival. Brain Res Mol Brain Res 2005;138:228–235. CrossRefGoogle ScholarPubMed
Lein, ES, Hawrylycz, MJ, Ao, Net al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007;445:168–176. CrossRefGoogle ScholarPubMed
Paizanis, E, Hamon, M, Lanfumey, L. Hippocampal neurogenesis, depressive disorders, and antidepressant therapy. Neural Plast 2007;2007:73754. CrossRefGoogle ScholarPubMed
Marcussen, AB, Flagstad, P, Kristjansen, PE, Johansen, FF, Englund, U. Increase in neurogenesis and behavioural benefit after chronic fluoxetine treatment in Wistar rats. Acta Neurol Scand 2008;117:94–100. Google ScholarPubMed
Qiu, G, Helmeste, DM, Samaranayake, ANet al. Modulation of the suppressive effect of corticosterone on adult rat hippocampal cell proliferation by paroxetine. Neurosci Bull 2007;23:131–136. CrossRefGoogle ScholarPubMed
Thakker-Varia, S, Krol, JJ, Nettleton, Jet al. The neuropeptide VGF produces antidepressant-like behavioral effects and enhances proliferation in the hippocampus. J Neurosci 2007;27:12156–12167. CrossRefGoogle ScholarPubMed