Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Archives of Psychiatry and Clinical Neuroscience
Published in: European Archives of Psychiatry and Clinical Neuroscience 2/2015

Open Access 01-03-2015 | Original Paper

Ribosomal DNA transcription in the dorsal raphe nucleus is increased in residual but not in paranoid schizophrenia

Authors: Marta Krzyżanowska, Johann Steiner, Ralf Brisch, Christian Mawrin, Stefan Busse, Katharina Braun, Zbigniew Jankowski, Hans-Gert Bernstein, Bernhard Bogerts, Tomasz Gos

Published in: European Archives of Psychiatry and Clinical Neuroscience | Issue 2/2015

Login to get access

Abstract

The central serotonergic system is implicated in the pathogenesis of schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 residual) schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in schizophrenia patients in the cumulative analysis of all DRN subnuclei (t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for residual schizophrenia versus paranoid schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in schizophrenia, particularly in residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.
Literature
1.
Abi-Dargham A (2007) Alterations of serotonin transmission in schizophrenia. Int Rev Neurobiol 78:133–164CrossRefPubMed
2.
Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chenn JJ, Mann JJ (2001) Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 25:892–903CrossRefPubMed
3.
Atkins M, Burgess A, Bottomley C, Riccio M (1997) Chlorpromazine equivalents: a consensus of opinion for both clinical and research applications. Psych Bull 21:224–226CrossRef
4.
Austin MC, Janosky JE, Murphy HA (2003) Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men. Mol Psychiatry 8:324–332CrossRefPubMed
5.
Bach H, Arango V (2012) Neuroanatomy of serotonergic abnormalities in suicide. In: Dwivedi Y (ed) The neurobiological basis of suicide. Taylor and Francis, New York, pp 11–27CrossRef
6.
Bach-Mizrachi H, Underwood MD, Kassir SA, Bakalian MJ, Sibille E, Tamir H, Mann JJ, Arango V (2006) Neuronal tryptophan hydroxylase mRNA expression in human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology 31:814–824CrossRefPubMed
7.
Bach-Mizrachi H, Underwood MD, Tin A, Ellis SP, Mann JJ, Arango V (2008) Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides. Mol Psychiatry 13:507–513CrossRefPubMedCentralPubMed
8.
Baker KG, Halliday GM, Törk I (1990) Cytoarchitecture of the human dorsal raphe nucleus. J Comp Neurol 301:147–161CrossRefPubMed
9.
Baumann B, Bielau H, Krell D, Agelink MW, Diekmann S, Wurthmann C, Trübner K, Bernstein HG, Danos P, Bogerts B (2002) Circumscribed numerical deficit of dorsal raphe neurons in mood disorders. Psychol Med 32:93–103PubMed
10.
Bernard R, Veh RW (2012) Individual neurons in the rat lateral habenular complex project mostly to the dopaminergic ventral tegmental area or to the serotonergic raphe nuclei. J Comp Neurol 520:2545–2558CrossRefPubMed
11.
Berninger B, Marty S, Zafra F, Berzaghi M, Thoenen H, Lindholm D (1995) GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro. Development 121:2327–2335PubMed
12.
Bielau H, Mawrin C, Krell D, Agelink MW, Trübner K, Davis R, Gos T, Bogerts B, Bernstein HG, Baumann B (2005) Differences in activation of the dorsal raphe nucleus depending on performance of suicide. Brain Res 1039:43–52CrossRefPubMed
13.
Bligh-Glover W, Kolli TN, Shapiro-Kulnane L, Dilley GE, Friedman L, Balraj E, Rajkowska G, Stockmeier CA (2000) The serotonin transporter in the midbrain of suicide victims with major depression. Biol Psychiatry 47:1015–1024CrossRefPubMed
14.
Boldrini M, Underwood MD, Mann JJ, Arango V (2005) More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides. Brain Res 1041:19–28CrossRefPubMed
15.
Boldrini M, Underwood MD, Mann JJ, Arango V (2008) Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides. J Psychiatr Res 42:433–442CrossRefPubMedCentralPubMed
16.
Bonkale WL, Murdock S, Janosky JE, Austin MC (2004) Normal levels of tryptophan hydroxylase immunoreactivity in the dorsal raphe of depressed suicide victims. J Neurochem 88:958–964CrossRefPubMed
17.
Bonkale WL, Turecki G, Austin MC (2006) Increased tryptophan hydroxylase immunoreactivity in the dorsal raphe nucleus of alcohol-dependent, depressed suicide subjects is restricted to the dorsal subnucleus. Synapse 60:81–85CrossRefPubMedCentralPubMed
18.
Bouras C, Kövari E, Hof PR, Riederer BM, Giannakopoulos P (2001) Anterior cingulate cortex pathology in schizophrenia and bipolar disorder. Acta Neuropathol 102:373–379PubMed
19.
Broadbelt K, Byne W, Jones LB (2002) Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex. Schizophr Res 58:75–81CrossRefPubMed
20.
Chana G, Landau S, Beasley C, Everall IP, Cotter D (2003) Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density. Biol Psychiatry 53:1086–1098CrossRefPubMed
21.
Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABAA, and glutamate receptors. J Neurosci 21:9917–9929PubMed
22.
Craven RM, Priddle TH, Cooper SJ, Crow TJ, Esiri MM (2005) The dorsal raphe nucleus in schizophrenia: a post mortem study of 5-hydroxytryptamine neurones. Neuropathol Appl Neurobiol 31:258–269CrossRefPubMed
23.
Dean B, Crossland N, Boer S, Scarr E (2008) Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia. Schizophr Res 104:185–197CrossRefPubMed
24.
de Bartolomeis A, Buonaguro EF, Iasevoli F (2013) Serotonin–glutamate and serotonin–dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins. Psychopharmacology 225:1–19CrossRefPubMed
25.
26.
Ding Q, Markesbery WR, Chen Q, Li F, Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer’s disease. J Neurosci 25:9171–9175CrossRefPubMed
27.
Ding Q, Markesbery WR, Cecarini V, Keller JN (2006) Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer’s disease. Neurochem Res 31:705–710CrossRefPubMed
28.
29.
Garcia-Moreno LM, Cimadevilla JM, Gonzalez-Pardo H, Zahonero MC, Arias JL (1997) NOR activity in hippocampal areas during the postnatal development and ageing. Mech Ageing Dev 97:173–181CrossRefPubMed
30.
Gomes C, Smith SC, Youssef MN, Zheng JJ, Hagg T, Hetman M (2011) RNA polymerase 1-driven transcription as a mediator of BDNF-induced neurite outgrowth. J Biol Chem 286:4357–4363CrossRefPubMedCentralPubMed
31.
Gonçalves L, Nogueira MI, Shammah-Lognado SJ, Metzger M (2009) Prefrontal afferents to the dorsal raphe nucleus in the rat. Brain Res Bull 78:240–247CrossRefPubMed
32.
Gos T, Krell D, Brisch R, Bielau H, Trübner K, Bernstein HG, Bogerts B (2007) The changes of AgNOR parameters of anterior cingulate pyramidal neurons are region-specific in suicidal and non-suicidal depressive patients. World J Biol Psychiatry 8:245–255CrossRefPubMed
33.
Gos T, Krell D, Brisch R, Bielau H, Trübner K, Steiner J, Bernstein HG, Bogerts B (2008) Demonstration of decreased activity of dorsal raphe nucleus neurons in depressed suicidal patients by the AgNOR staining method. J Affect Disord 111:251–260CrossRefPubMed
34.
Gos T, Krell D, Bielau H, Steiner J, Mawrin C, Trübner K, Brisch R, Bernstein HG, Jankowski Z, Bogerts B (2009) Demonstration of disturbed activity of orbitofrontal pyramidal neurons in depressed patients by the AgNOR staining method. J Affect Disord 118:131–138CrossRefPubMed
35.
Gos T, Krell D, Bielau H, Steiner J, Trübner K, Brisch R, Bernstein HG, Jankowski Z, Bogerts B (2009) Demonstration of disturbed activity of external globus pallidus projecting neurons in depressed patients by the AgNOR staining method. J Affect Disord 119:149–155CrossRefPubMed
36.
Gos T, Krell D, Bielau H, Steiner J, Mawrin C, Trübner K, Brisch R, Bernstein HG, Jankowski Z, Bogerts B (2010) Demonstration of disturbed activity of the lateral amygdaloid nucleus projection neurons in depressed patients by the AgNOR staining method. J Affect Disord 126:402–410CrossRefPubMed
37.
Gos T, Steiner J, Krell D, Bielau H, Mawrin C, Krzyżanowski M, Brisch R, Pieśniak D, Bernstein HG, Jankowski Z, Braun K, Bogerts B (2013) Ribosomal DNA transcription in the anterior cingulate cortex is decreased in unipolar but not bipolar depression. Psychiatry Res 210:338–345CrossRefPubMed
38.
Gundersen HJG, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcussen N, Møller A, Nielsen K, Nyengaard JR, Pakkenberg B et al (1988) The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96:857–881CrossRefPubMed
39.
Harrison PJ (1999) The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122:593–624CrossRefPubMed
40.
Hayashida M, Miyaoka T, Tsuchie K, Yasuda H, Wake R, Nishida A, Inagaki T, Toga T, Nagami H, Oda T, Horiguchi J (2009) Hyperbilirubinemia-related behavioral and neuropathological changes in rats: a possible schizophrenia animal model. Prog Neuropsychopharmacol Biol Psychiatry 33:581–588CrossRefPubMed
41.
42.
Jacobs BL, Azmitia EC (1992) Structure and function of the brain serotonin system. Physiol Rev 72:165–229PubMed
43.
Jakab RL, Goldman-Rakic PS (1998) 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci USA 95:735–740CrossRefPubMedCentralPubMed
44.
Jankowski MP, Sesack SR (2004) Prefrontal cortical projections to the rat dorsal raphe nucleus: ultrastructural features and associations with serotonin and γ-aminobutyric acid neurons. J Comp Neurol 468:518–529CrossRefPubMed
45.
Lee HS, Kim MA, Valentino RJ, Waterhouse BD (2003) Glutamatergic afferent projections to the dorsal raphe nucleus of the rat. Brain Res 963:57–71CrossRefPubMed
46.
Lloyd KG, Farley IJ, Deck JHN, Horynkiewicz O (1974) Serotonin and 5-hydroxyindoleacetic acid in discrete areas of the brainstem of suicide victims and control patients. Adv Biochem Psychopharmacol 11:387–397PubMed
47.
Matthews PR, Harrison PJ (2012) A morphometric, immunohistochemical, and in situ hybridization study of the dorsal raphe nucleus in major depression, bipolar disorder, schizophrenia, and suicide. J Affect Disord 137:125–134CrossRefPubMedCentralPubMed
48.
McGowan PO, Szyf M (2010) The epigenetics of social adversity in early life: implications for mental health outcomes. Neurobiol Dis 39:66–72CrossRefPubMed
49.
Meltzer HY (2012) Serotonergic mechanisms as targets for existing and novel antipsychotics. Handb Exp Pharmacol 212:87–124CrossRefPubMed
50.
Mennel HD, Müller I (1994) Morphometric investigation on nuclear and nucleolar arrangement and AgNOR content in the rat hippocampus under normal and ischemic conditions. Exp Toxicol Pathol 46:491–501CrossRefPubMed
51.
Muguruza C, Moreno JL, Umali A, Callado LF, Meana JJ, González-Maeso J (2013) Dysregulated 5-HT2A receptor binding in postmortem frontal cortex of schizophrenic subjects. Eur Neuropsychopharmacol 23:852–864CrossRefPubMedCentralPubMed
52.
Peyron C, Petit JM, Rampon C, Jouvet M, Luppi PH (1998) Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods. Neuroscience 82:443–468CrossRefPubMed
53.
54.
Ploton D, Menager M, Jeannesson P, Himber G, Pigeon F, Adnet JJ (1986) Improvement in the staining and in the visualization of the argyrophilic proteins of the nucleolar organiser region at the optical level. Histochem J 18:5–14CrossRefPubMed
55.
Ploton D, Visseaux-Coletto B, Canellas JC, Bourzat C, Adnet JJ, Lechki C, Bonnet N (1992) Semiautomatic quantification of silver-stained nucleolar organiser regions in tissue sections and cellular smears. Anal Quant Cytol Histol 14:14–23PubMed
56.
Ploton D (1994) Structure and molecular organization of the nucleolus. Zentralbl Pathol 140:3–6PubMed
57.
Polak M, Haymaker W, Johnson JE, D’Amelio F (1982) Neuroglia and their reactions. In: Haymaker W, Adams RD (eds) Histology and histopathology of nervous system. Charles C. Thomas Publishing, Springfield, pp 363–480
58.
Preuss UW, Zetzsche T, Pogarell O, Mulert C, Frodl T, Müller D, Schmidt G, Born C, Reiser M, Möller HJ, Hegerl U, Meisenzahl EM (2010) Anterior cingulum volumetry, auditory P300 in schizophrenia with negative symptoms. Psychiatry Res 183:133–139CrossRefPubMed
59.
Raska I, Shaw PJ, Cmarko D (2006) New insights into nucleolar architecture and activity. Int Rev Cytol 255:177–235CrossRefPubMed
60.
Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LH, Baaré W, Svarer C, Lublin H, Knudsen GM, Glenthoj B (2010) Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia. Arch Gen Psychiatry 67:9–16CrossRefPubMed
61.
Rey M-J, Schulz P, Costa C, Dick P, Tissot R (1989) Guidelines for the dosage of neuroleptics. I: chlorpromazine equivalents of orally administrated neuroleptics. Int Clin Psychopharmacol 4:95–104CrossRefPubMed
62.
Rüschoff J, Elsässer HP, Adler G (1995) Correlation of nucleolar organiser regions with secretory and regenerative process in experimental cerulein-induced pancreatitis in the rat. Pancreas 11:154–159CrossRefPubMed
63.
Sanfilipo M, Lafargue T, Rusinek H, Arena L, Loneragan C, Lautin A, Feiner D, Rotrosen J, Wolkin A (2000) Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms. Arch Gen Psychiatry 57:471–480CrossRefPubMed
64.
Sharp T, Boothman L, Raley J, Quérée P (2007) Important messages in the ‘post’: recent discoveries in 5-HT neurone feedback control. Trends Pharmacol Sci 28:629–636CrossRefPubMed
65.
66.
67.
Steiner J, Bernstein HG, Bielau H, Farkas N, Winter J, Dobrowolny H, Brisch R, Gos T, Mawrin C, Myint AM, Bogerts B (2008) S100B-immunopositive glia is elevated in paranoid as compared to residual schizophrenia: a morphometric study. J Psychiatr Res 42:868–876CrossRefPubMed
68.
Steiner J, Schmitt A, Schroeter ML, Bogerts B, Falkai P, Turck CW, Martins-de-Souza D (2014) S100B is downregulated in the nuclear proteome of schizophrenia corpus callosum. Eur Arch Psychiatry Clin Neurosci 264:311–316CrossRefPubMed
69.
Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G (1998) Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci 18:7394–7401PubMed
70.
Takayanagi M, Wentz J, Takayanagi Y, Schretlen DJ, Ceyhan E, Wang L, Suzuki M, Sawa A, Barta PE, Ratnanather JT, Cascella NG (2013) Reduced anterior cingulate gray matter volume and thickness in subjects with deficit schizophrenia. Schizophr Res 150:484–490CrossRefPubMedCentralPubMed
71.
Underwood MD, Khaibulina AA, Ellis SP, Moran A, Rice PM, Mann JJ, Arango V (1999) Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims. Biol Psychiatry 46:473–483CrossRefPubMed
72.
Van Bockstaele EJ, Biswas A, Pickel VM (1993) Topography of serotonin neurons in the dorsal raphe nucleus that send axon collaterals to the rat prefrontal cortex and nucleus accumbens. Brain Res 624:188–198CrossRefPubMed
73.
Varga V, Székely AD, Csillag A, Sharp T, Hajós M (2001) Evidence for a role of GABA interneurons in the cortical modulation of midbrain 5-hydroxytryptamine neurones. Neuroscience 106:783–792CrossRefPubMed
74.
Varga V, Kocsis B, Sharp T (2003) Electrophysiological evidence for convergence of inputs from the medial prefrontal cortex and lateral habenula on single neurons in the dorsal raphe nucleus. Eur J Neurosci 17:280–286CrossRefPubMed
75.
Vasudeva RK, Lin RC, Simpson KL, Waterhouse BD (2011) Functional organization of the dorsal raphe efferent system with special consideration of nitrergic cell groups. J Chem Neuroanat 41:281–293CrossRefPubMed
76.
Vázquez-Borsetti P, Cortés R, Artigas F (2009) Pyramidal neurons in rat prefrontal cortex projecting to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors. Cereb Cortex 19:1678–1686CrossRefPubMedCentralPubMed
77.
Willins DL, Deutch AY, Roth BL (1997) Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:79–82CrossRefPubMed
78.
Wilson MA, Molliver ME (1991) The organization of serotonergic projections to cerebral cortex in primates: retrograde transport studies. Neuroscience 44:555–570CrossRefPubMed
79.
Zafra F, Castrene E, Thoenen H, Lindholm D (1991) Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci USA 88:10037–10041CrossRefPubMedCentralPubMed
Metadata
Title
Ribosomal DNA transcription in the dorsal raphe nucleus is increased in residual but not in paranoid schizophrenia
Authors
Marta Krzyżanowska
Johann Steiner
Ralf Brisch
Christian Mawrin
Stefan Busse
Katharina Braun
Zbigniew Jankowski
Hans-Gert Bernstein
Bernhard Bogerts
Tomasz Gos
Publication date
01-03-2015
Publisher
Springer Berlin Heidelberg
Published in
European Archives of Psychiatry and Clinical Neuroscience / Issue 2/2015
Print ISSN: 0940-1334
Electronic ISSN: 1433-8491
DOI
https://doi.org/10.1007/s00406-014-0518-4

Other articles of this Issue 2/2015

European Archives of Psychiatry and Clinical Neuroscience 2/2015 Go to the issue

Original Paper

Evaluation of an integrated care program for schizophrenia: concept and study design

Original Paper

Antipsychotic-induced parkinsonism is associated with working memory deficits in schizophrenia-spectrum disorders

Short Communication

Lower phosphorylated glycogen synthase kinase-3B levels in platelets of patients with schizophrenia: increment by olanzapine treatment

Original Paper

What are residual symptoms in schizophrenia spectrum disorder? Clinical description and 1-year persistence within a naturalistic trial

Editorial

Schizophrenia spectrum and related neuropathology

Original Paper

Influence of DGKH variants on amygdala volume in patients with bipolar affective disorder and schizophrenia