Top

Published in:

01-07-2008 | Basic Neurosciences, Genetics and Immunology - Original Article

Neurotrophin and neuropeptide expression in mouse brain is regulated by knockout of the norepinephrine transporter

Authors: B. Haenisch, R. Gilsbach, H. Bönisch

Published in: Journal of Neural Transmission | Issue 7/2008

Abstract

Neurotrophins [e.g. nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] and neuropeptides such as corticotropin-releasing factor (CRF) are reported to contribute to the action of antidepressants (ADs). Norepinephrine transporter (NET) knockout (NETKO) mice represent a model of chronic AD treatment. In the present study, we examined brain-region-specific regulations of NT-3, NGF, BDNF and CRF at the mRNA and protein level in NET wild-type (NETWT) and NETKO mice by means of quantitative real-time PCR (qPCR) and two-site enzyme-linked immunosorbent assays (ELISAs), respectively. NETKO-induced changes were detected for NT-3 in olfactory bulb, brainstem and whole brain at the mRNA and for olfactory bulb at the protein level, for NGF mRNA and protein in olfactory bulb, cerebellum and brainstem and for CRF mRNA and protein in the hippocampus. In contrast, BDNF levels remained unaltered. Our results suggest that NETKO mice represent a useful model to examine gene regulation of downstream targets potentially involved in the action of ADs. We could delineate NT-3, NGF and CRF as being regulated in distinct brain regions by KO of the NET.

Alfonso J, Pollewick GD, van der Hart MG, Flügge G, Fuchs E, Frasch AC (2004) Identification of genes regulated by chronic psychosocial stress and antidepressant treatment in the hippocampus. Eur J Neurosci 19:659–666PubMedCrossRef

Altar CA (1999) Neurotrophins and depression. Trends Pharmacol Sci 20:59–61PubMedCrossRef

Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM (2003) Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 54:703–709PubMedCrossRef

Arenas E, Persson H (1994) Neurotrophin-3 prevents the death of adult central noradrenergic neurons in vivo. Nature 367:368–371PubMedCrossRef

Arzt E, Holsboer F (2006) CRF signalling: molecular specificity for drug targeting in the CNS. Trends Pharmacol Sci 27:531–538PubMedCrossRef

Bale TL (2006) Stress sensitivity and the development of affective disorders. Horm Behav 50:529–533PubMedCrossRef

Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151PubMedCrossRef

Bissette G, Klimek V, Pan J, Stockmeier C, Ordway G (2003) Elevated concentrations of CRF in the locus coeruleus of depressed subjects. Neuropsychopharmacology 28:1328–1335PubMedCrossRef

Bönisch H and Brüss M (2006) The norepinephrine transporter in physiology and disease. In: Sitte HH, Freissmuth M (eds) Neurotransmitter transporters, Handbook of experimental pharmacology, vol 175. Springer, Heidelberg, pp 485–524

Castren E (2004) Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol 4:58–64PubMedCrossRef

Castren E (2005) Is mood chemistry? Nat Rev Neurosci 6:241–246PubMedCrossRef

Chen Y, Bender RA, Frotscher M, Baram TZ (2001) Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci 21:7171–7181PubMed

Chen Y, Brunson KL, Adelmann G, Bender RA, Frotscher M, Baram TZ (2004) Hippocampal corticotropin releasing hormone: pre- and postsynaptic location and release by stress. Neuroscience 126:533–540PubMedCrossRef

Coppell AL, Pei QA, Zetterström TSC (2003) Bi-phasic change in BDNF gene expression following antidepressant drug treatment. Neuropharmacology 44:903–910PubMedCrossRef

Cryan JF, Holmes A (2005) The ascent of mouse: advantages in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790PubMedCrossRef

Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E (2001) Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci 98:12796–12801PubMedCrossRef

de Bellis MD, Gold PW, Geracioti Jr TD, Listwak SJ, Kling MA (1993) Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am J Psychiatry 150:656–657PubMed

de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475PubMedCrossRef

Duman RS (2004) Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med 5:11–25PubMedCrossRef

Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597–606PubMed

Dziedzicka-Wasylewska M, Faron-Gorecka A, Kusmider M, Drozdowska E, Rogoz Z, Siwanowicz J, Caron MG, Bönisch H (2006) Effect of antidepressant drugs in mice lacking the norepinephrine transporter. Neuropsychopharmacology 31:2424–2432PubMedCrossRef

Eisch AJ, Bolanos CA, de Witt J, Simonak RD, Pudiak CM, Barrot M, Verhaagen J, Nestler EJ (2003) Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry 54:994–1005PubMedCrossRef

Foreman PJ, Taglialatela G, Angelucci L, Turner PC, Perez-Polo JR (1993) Nerve growth factor and p75 NGFR factor mRNA change in rodent CNS following stress activation of the hypothalamo-pituitary-adrenocortical axis. J Neurosci 36:10–18CrossRef

Gilsbach R, Faron-Gorecka A, Rogoz Z, Brüss M, Caron MG, Dziedzicka-Wasylewska M, Bönisch H (2006a) Norepinephrine transporter knockout-induced up-regulation of brain alpha2A/C-adrenergic receptors. J Neurochem 96:1111–1120PubMedCrossRef

Gilsbach R, Kouta M, Bönisch H, Brüss M (2006b) Comparison of in vitro and in vivo reference genes for internal standardization of real-time PCR data. Biotechniques 40:173–177PubMed

Hashimoto K, Shimizu E, Iyo M (2004) Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev 45:104–114PubMedCrossRef

Hellweg R, Lang UE, Nagel M, Baumgartner A (2002) Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats. Mol Psychiatry 7:604–608PubMedCrossRef

Hellweg R Zueger M, Fink K, Hörtnagl H, Gass P (2007) Olfactory bulbectomy in mice leads to increased BDNF levels and decreased serotonin turnover in depression-related brain areas. Neurobiol Dis 25:1–7CrossRef

Hock C, Heese K, Müller-Spahn F, Huber P, Riesen W, Nitsch RM, Otten U (2000) Increased cerebrospinal fluid levels of neurotrophin 3 (NT-3) in elderly patients with major depression. Mol Psychiatry 5:510–513PubMedCrossRef

Hofer M, Pagliusi SR, Hohn A, Leibrock J, Barde YA (1990) Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 9:2459–2464PubMed

Holsboer F (2003) Corticotropin-releasing hormone modulators and depression. Curr Opin Investig Drugs 4:46–50PubMed

Ising M, Zimmermann US, Künzel HE, Uhr M, Foster AC, Learned-Coughlin SM, Holsboer F, Grigoriadis DE (2007) High-affinity CRF1 receptor antagonist NBI-34041: Preclinical and clinical data support safety and efficacy in attenuating elevated stress response. Neuropsychopharmacology 32:1941–1949PubMedCrossRef

Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA (2003) Noradrenergic and serotoninergic blockade inhibits BDNF mRNA activation following exercise and antidepressants. Pharmacol Biochem Behav 75:81–88PubMedCrossRef

Katoh-Semba R, Takeuchi IK, Semba R, Kato K (1997) Distribution of brain-derived neurotrophic factor in rats and its changes with the development in the brain. J Neurochem 69:34–42PubMedCrossRef

Keck ME, Ohl F, Holsboer F, Müller M (2005) Listening to mutant mice: a spotlight on the role of CRF/CRF receptor systems in affective disorders. Neurosci Biobehav Rev 29:867–889PubMedCrossRef

Kim SJ, Park SH, Choi SH, Moon BH, Lee KJ, Kang SW, Lee MS, Choi SH, Chun BG, Shin KH (2006) Effects of repeated tianeptine treatment on CRF mRNA expression in non-stressed and chronic mild stress-exposed rats. Neuropharmacology 50:824–833PubMedCrossRef

Levi-Montalcini R, Skaper SD, Toso RD, Petrelli L, Leon A (1996) Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci 19:514–520PubMedCrossRef

Lorang D, Amara SG, Simerly RB (1994) Cell-type-specific expression of catecholamine transporters in the rat brain. J Neurosci 14:4903–4914PubMed

Maisonpierre PC, Belluscio L, Friedman B, Alderson RF, Wiegand SJ, Furth ME, Lindsay RM, Yancopoulos GD (1990) NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron 5:501–509PubMedCrossRef

Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110PubMed

Malberg JE, Blendy JA (2005) Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci 26:631–638PubMedCrossRef

Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, Gray NA, Zarate CA, Charney DS (2003) Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 53:707–742PubMedCrossRef

Nakane T, Audhya T, Hollander CS, Schlesinger DH, Kardos P, Brown C, Passarelli J (1986) Corticotrophin-releasing factor in extra-hypothalamic brain of the mouse: demonstration by immunoassay and immunoneutralization of bioassayable activity. J Endocrinol 111:143–149PubMedCrossRef

Nestler EJ, Barrot M, DiLeone RJ, Eisch A, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25PubMedCrossRef

Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547PubMed

Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45PubMedCrossRef

Post RM (2007) Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. J Psychiatr Res 41:979–990PubMedCrossRef

Reul JM, Holsboer F (2002) Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2:23–33PubMedCrossRef

Risbrough VB, Stein MB (2006) Role of corticotropin releasing factor in anxiety disorders: a translational research perspective. Horm Behav 50:550–561PubMedCrossRef

Russo-Neustadt AA, Alejandre H, Garcia C, Ivy AS, Chen MJ (2004) Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology 29:2189–2199PubMedCrossRef

Rylett RJ, Williams LR (1994) Role of neurotrophins in cholinergic-neuron function in the adult and aged CNS. Trends Neurosci 17:486–490PubMedCrossRef

Scaccianoce S, Lombardo K, Angelucci L (2000) Nerve growth factor brain concentration and stress changes depend on type of stressor and age. Int J Dev Neurosci 18:469–479PubMedCrossRef

Schulte-Herbrüggen O, Chourbaji S, Müller H, Danker-Hopfe H, Brandwein C, Gass P, Hellweg R (2006) Differential regulation of nerve growth factor and brain-derived neurotrophic factor in a mouse model of learned helplessness. Exp Neurol 202:404–409PubMedCrossRef

Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioural models of depression. J Neurosci 22:3251–3261PubMed

Smith MA, Makino S, Altemus M, Michelson D, Hong SK, Kvetnansky R, Post RM (1995) Stress and antidepressants differentially regulate neurotrophin 3 mRNA expression in the locus coeruleus. Proc Natl Acad Sci 92:8788–8792PubMedCrossRef

Spillantini MG, Aloe L, Alleva E, De Simone R, Goedert M, Levi-Montalcini R (1989) Nerve growth factor mRNA and protein increase in hypothalamus in a mouse model of aggression. Proc Natl Acad Sci 86:8555–8559PubMedCrossRef

Stout SC, Owens MJ, Nemeroff CB (2002) Regulation of corticotropin-releasing factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment. J Pharmacol Exp Ther 300:1085–1092PubMedCrossRef

von Richthofen S, Lang UE, Hellweg R (2003) Effects of different kinds of acute stress on nerve growth factor content in rat brain. Brain Res 987:207–213CrossRef

Wang YM, Xu F, Gainetdinov RR, Caron MG (1999) Genetic approaches to studying norepinephrine function: knockout of the mouse norepinephrine transporter gene. Biol Psychiatry 46:1124–1130PubMedCrossRef

Whittemore SR, Ebendal T, Lärkfors L, Olson L, Seiger A, Strömberg I, Persson H (1986) Developmental and regional expression of ß nerve growth factor messenger RNA and protein in the rat central nervous system. Proc Natl Acad Sci 83:817–821PubMedCrossRef

Willner P (1990) Animal models of depression: an overview. Pharmacol Ther 45:425–455PubMedCrossRef

Xu F, Gainetdinov RR, Wetsel WC, Jones SR, Bohn LM, Miller GW, Wang YM, Caron MG (2000) Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci 3:465–471PubMedCrossRef

Zhang JM, Dix J, Langtimm-Sedlack CJ, Trusk T, Schroeder B, Hoffmann R, Strosberg AD, Winslow JW, Sieber-Blum M (1997) Neurotrophin-3- and norepinephrine-mediated adrenergic differentiation and the inhibitory action of desipramine and cocaine. J Neurobiol 32:262–280PubMedCrossRef

Title: Neurotrophin and neuropeptide expression in mouse brain is regulated by knockout of the norepinephrine transporter
Authors: B. Haenisch
R. Gilsbach
H. Bönisch
Publication date: 01-07-2008
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 7/2008
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-008-0039-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Neurotrophin and neuropeptide expression in mouse brain is regulated by knockout of the norepinephrine transporter

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2008

Multiple aspects related to self-awareness and the awareness of others: an electroencephalography study

A 1H magnetic resonance spectroscopy study in adults with obsessive compulsive disorder: relationship between metabolite concentrations and symptom severity

Celecoxib as an in vivo probe of cyclooxygenase-2 mechanisms underlying retrograde amnesia in an animal model of ECT

Decreased blood–brain barrier P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSA

Microarray expression analysis reveals genetic pathways implicated in C621 synphilin-1-mediated toxicity

MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats