Skip to main content

Gender-Dependent Modulation of Brain Monoamines and Anxiety-like Behaviors in Mice with Genetic Serotonin Transporter and BDNF Deficiencies

Cellular and Molecular Neurobiology volume 26, pages 753–778 (2006)Cite this article

1. Brain-derived neurotrophic factor (BDNF) supports serotonergic neuronal development and our recent study found that heterozygous mice lacking one BDNF gene allele interbred with male serotonin transporter (SERT) knockout mice had greater reductions in brain tissue serotonin concentrations, greater increases in anxiety-like behaviors and greater ACTH responses to stress than found in the SERT knockout mice alone.

2. We investigated here whether there might be gender differences in these consequences of combined SERT and BDNF deficiencies by extending the original studies to female mice, and also to an examination of the effects of ovariectomy and tamoxifen in these female mice, and of 21-day 17-β estradiol implantation to male mice.

3. We found that unlike the male SERT×BDNF-deficient mice, female SERT×BDNF mice appeared protected by their gender in having significantly lesser reductions in serotonin concentrations in hypothalamus and other brain regions than males, relative to controls. Likewise, in the elevated plus maze, female SERT×BDNF-deficient mice demonstrated no increases in the anxiety-like behaviors previously found in males.

4. Furthermore, female SERT×BDNF mice did not manifest the ∼40% reduction in the expression of TrkB receptors or the ∼30% reductions in dopamine and its metabolites that male SERT×BDNF did. After estradiol implantation in male SERT×BDNF mice, hypothalamic serotonin was significantly increased compared to vehicle-implanted mice. These findings support the hypothesis that estrogen may enhance BDNF function via its TrkB receptor, leading to alterations in the serotonin circuits, which modulate anxiety-like behaviors.

5. This double-mutant mouse model contributes to the knowledge base that will help in understanding gene×gene×gender interactions in studies of SERT and BDNF gene polymorphisms in human genetic diseases such as anxiety disorders and depression.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.
Fig. 8.
Fig. 9.

REFERENCES

  • Allen, A. L., and McCarson, K. E. (2005). Estrogen increases nociception-evoked brain-derived neurotrophic factor gene expression in the female rat. Neuroendocrinology 81:193–199.

    PubMed  CAS  Google Scholar 

  • Andrews, A. M., and Murphy, D. L. (1993). Sustained depletion of cortical and hippocampal serotonin and norepinephrine but not striatal dopamine by 1-methyl-4-(2′aminophenyl)- 1,2,3,6-tetrahydropyridine (2′-NH2–MPTP): A comparative study with 2′-CH3-MPTP and MPTP. J. Neurochem. 60:1167–1170.

    PubMed  CAS  Google Scholar 

  • Armando, I., Tjurmina, O. A., Li, Q., Murphy, D. L., and Saavedra, J. M. (2003). The serotonin transporter is required for stress-evoked increases in adrenal catecholamine synthesis and angiotension II AT(2) receptor expression. Neuroendocrinology 78:217–225.

    PubMed  CAS  Google Scholar 

  • Axelrod, J. (2003). Journey of a late blooming biochemical neuroscientist. J. Biol. Chem. 278:367–373.

    Google Scholar 

  • Axelrod, J., and Kopin, I. J. (1969). The uptake, storage, release and metabolism of noradrenaline in sympathetic nerves. Prog. Brain Res. 31:21–32.

    PubMed  CAS  Article  Google Scholar 

  • Becker, J. B. (1999). Gender differences in dopamine function in striatum and nucleus accumbens. Pharmacol. Biochem. Behav. 64:803–812.

    PubMed  CAS  Google Scholar 

  • Bengel, D., Murphy, D. L., Andrews, A. M., Wichems, C. H., Feltner, D., Heils, A., Mossner, R., Westphal, H., and Lesch, K.-P. (1998). Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxy-methamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol. Pharmacol. 53:649–655.

    PubMed  CAS  Google Scholar 

  • Berchtold, N. C., Kesslak, J. P., Pike, C. J., Adiard, P. A., and Cotmau, C. W. (2001). Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus. Eur. J. Neurosci. 14:1992–2002.

    PubMed  CAS  Google Scholar 

  • Berton, O., McClung, C. A., Dileone, R. J., Krishnan, V., Renthal, W., Russo, S. J., Graham, D., Tsankova, N. M., Bolanos, C. A., Rios, M., Monteggia, L. M., Self, D. W., and Nestler, E. J. (2006). Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868.

    PubMed  CAS  Google Scholar 

  • Bonhoeffer, T. (1996). Neurotrophins and activity-dependent development of the neocortex. Curr. Opin. Neurobiol. 6:119–126.

    PubMed  CAS  Google Scholar 

  • Brito, V. I., Carrer, H. F., and Cambiasso, M. J. (2004). Inhibition of tyrosine kinase receptor type B synthesis blocks axogenic effect of estradiol on rat hypothalamic neuron in vitro. Eur. J. Neurosci. 20:331–337.

    PubMed  CAS  Google Scholar 

  • Carroll, P., Lewin, G. R., Koltzenburg, M., Toyka, K. V., and Thoenen, H. (1998). A role for BDNF in mechanosensation. Nat. Neurosci. 1:42–46.

    PubMed  CAS  Google Scholar 

  • Carter, A. R., Chen, C., Schwartz, P. M., and Segal, R. A. (2002). Brain-derived neurotrophic factors, cerebellar plasticity, and synaptic ultrastructure. J. Neurosci. 22(4):1316–1327.

    PubMed  CAS  Google Scholar 

  • Caspi, A., Sugden, K., Moffitt, T. E., Tayor, A., Craig, I. W., Harrington, J. M., Mill, J., Martin, J., Braithwaite, A., and Poulton, R. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 301:386–389.

    PubMed  CAS  Google Scholar 

  • Castren, E., Thoenen, H., and Lindholm, D. (1995). Brain-derived neurotrophic factor messenger RNA is expressed in the septum, hypothalamus and in adrenergic brain stem nuclei of adult rat brain and increased by osmotic stimulation in the paraventricular nucleus. Neuroscience 64:71–80.

    PubMed  CAS  Google Scholar 

  • Chen, J. J., Li, Z., Pan, H., Murphy, D. L., Tamir, H., Koepsell, H., and Gershon, M. D. (2001). Maintence of serotonin in the interestinal mucosa and ganglion of that lack the high-affinity serotonin transporter: Abnormal interestinal motility and the expression of cation transporters. J. Neurosci. 21(16):6348–6361.

    PubMed  CAS  Google Scholar 

  • Chen, Z. Y., Patel, P. D., Sant, G., Meng, C. X., Teng, K. K., Hempstead, B., and Lee, F. S. (2004). Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J. Neurosci. 24(18):4401–4411.

    PubMed  CAS  Google Scholar 

  • Conover, J. C., Erickson, J. T., Kate, D. M., Bianchi, L. M., Poueymirou, W. T., McClain, J., Pan, L., Helgren, M., Ip, N. Y., Boland, P., Friendman, B., Weigand, S., Vejsada, R., Kate, A. C., DeChiara, T. M., and Yancopoulos, G. D. (1995). Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature 375:235–238.

    PubMed  CAS  Google Scholar 

  • Cooke, B. M., and Woolley, C. S. (2005). Gonadal hormone modulation of dendrites in the mammalian CNS. J. Neurobiol. 64(1):34–46.

    PubMed  CAS  Google Scholar 

  • Davies, A. M., Thoenen, H., and Barde, Y.-A. (1986). The response of chick sensory neurons to brain-derived neurotrophic factor. J. Neurosci. 6(7):1897–1904.

    PubMed  CAS  Google Scholar 

  • Dluzen, D. E., Anderson, L. I., McDermott, J. L., Kucera, J., and Walro, J. M. (2002). Striatal dopamine output is compromised within ± BDNF mice. Synapse 43:112–117.

    PubMed  CAS  Google Scholar 

  • Eaton, M. J., Staley, J. K., Globus, M. Y., and Whittemore, S. R. (1995). Developmental regulation of early serotonergic neuronal differentiation: The role of brain-derived neurotrophic factor and membrane depolarization. Dev. Biol. 170(1):169–182.

    PubMed  CAS  Google Scholar 

  • Eaton, M. J., and Whittemore, S. R. (1996). Autocrine BDNF secretion enhances the survival and serotonergic differentiation of raphe neuronal precursor cells grafted into the adult rat CNS. Exp. Neurol. 140:105–114.

    PubMed  CAS  Google Scholar 

  • Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., Zaitsev, E., Gold, B., Goldman, D., Dean, M., Lu, B., and Weinberger, D. R. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269.

    PubMed  CAS  Google Scholar 

  • Ernfors, P., Merlio, J. P., and Persson, H. (1992). Cells expressing mRNA for neurotrophins and their receptors during embryonic rat development. Eur. J. Neurosci. 4:1140–1158.

    PubMed  Google Scholar 

  • Ernfors, P., Lee, K. F., and Jaenish, R. (1994). Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368:147–150.

    PubMed  CAS  Google Scholar 

  • Fanous, A. H., Neale, M. C., Straub, R. E., Webb, B. T., O’Neill, A. F., Walsh, D., and Kendles, K. S. (2004). Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: A family based association study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 125:69–78.

    PubMed  Google Scholar 

  • Franklin, T. B., and Perrot-Sinal, T. S. (2006). Sex and ovarian steroids modulate brain-derived neurotrophic factor (BDNF) protein levels in rat hippocampus under stressful and non-stressful conditions. Psychoneuroendocrinology 31:38–48.

    PubMed  CAS  Google Scholar 

  • Frechilla, D., Insausti, R., Ruiz-Golvano, P., Garcia-Osta, A., Rubio, M. P., Almendral, J. M., and Del Rio, J. (2000). Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum. Brain Res. Mol. Brain Res. 76(2):306–314.

    PubMed  CAS  Google Scholar 

  • Gainetdinov, R. R., Sotnikova, T. D., and Caron, M. G. (2002). Monoamine transporter pharmacology and mutant mice. Trends Pharmacol. Sci. 23(8):367–373.

    PubMed  CAS  Google Scholar 

  • Galter, D., and Unsicker, K. (2000). Brain-derived neurotrophic factor and TrkB are essential for cAMP-mediated induction of the serotonergic neuronal phenotype. J. Neurosci. Res. 61(3):295–301.

    PubMed  CAS  Google Scholar 

  • Gibbs, R. B. (1998). Levels of TrkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement. Brain Res. 787:259–268.

    PubMed  CAS  Google Scholar 

  • Gibbs, R. B. (1999). Treatment with estrogen and progesterone affects relative levels of brain-derived neurotrophic factor mRNA and protein in different regions of the adult rat brain. Brain Res. 844:20–27.

    PubMed  CAS  Google Scholar 

  • Goggi, J., Pullar, I. A., Carney, S. L., and Bradford, H. F. (2002). Modulation of neurotransmitter release induced by brain-derived neurotrophic factor in rat brain striatal slices in vitro. Brain Res. 941(1–2):34–42.

    PubMed  CAS  Google Scholar 

  • Hall, D., Dhilla, A., Charambous, A., Gogos, J. A., and Karayiorgou, M. (2003). Sequence variants of the BDNF-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am. J. Hum. Genet. 73(2):370–376.

    PubMed  CAS  Google Scholar 

  • Holmes, A., Yang, R. J., Murphy, D. L., and Crawley, J. N. (2001). Abnormal emotional behaviors and age-related obesity in 5-HT transporter deficient mice. Soc. Neurosci. Abstr. 27:985.7.

    Google Scholar 

  • Holmes, A., Murphy, D. L., and Crawley, J. N. (2002). Reduced aggression in mice lacking the 5-HT transporter. Psychopharmacology 161:160–167.

    PubMed  CAS  Google Scholar 

  • Holmes, A., Yang, R. J., Crawley, J. N., Lesch, K.-P., and Murphy, D. L. (2003). Mice lacking the serotonin transporter exhibit 5-HT 1A receptor-mediated abnormalites in anxiety-like and exploratory behavior. Neuropsychopharmacology 28:2077–2088.

    PubMed  CAS  Google Scholar 

  • Hyman, C., Hofer, M., Barde, Y.-A., Juhasz, M., Yancopoulos, R. M., Squinto, S. P., and Lindsay, R. M. (1991). BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350:230–232.

    PubMed  CAS  Google Scholar 

  • Jones, K. R., Farnas, I., Backus, C., and Reichardt, L. F. (1994). Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 76:989–999.

    PubMed  CAS  Google Scholar 

  • Jones, M. D., and Lucki, I. (2005). Sex differences in the regulation of serotonergic transmission and behavior in 5-HT receptor knockout mice. Neuropsychopharmacology 30:1039–1047.

    PubMed  CAS  Google Scholar 

  • Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., Grasso, D., Lipschitz, D., Houshyar, S., Krystal, J. H., and Gelernter, J. (2006). Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol. Psychiatry [E-pub. ahead of print].

  • Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., and Aubry, J.-M. (2002). Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 109:143–148.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  • Kernie, S. G., Liebl, D. J., and Parada, L. F. (2000). BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 19:1290–1300.

    PubMed  CAS  Google Scholar 

  • Kim, D. K., Tolliver, T. J., Huang, S. J., Martin, B. J., Andrews, A. M., Wichems, C., Holmes, A., Lesch, K. P., and Murphy, D. L. (2005). Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter. Neuropharmacology 49:798–810.

    PubMed  CAS  Google Scholar 

  • Kolbeck, R., Bartke, I., Eberle, W., and Brade, Y.-A. (1999). Brain-derived neurotrophic factor levels in the nervous system of wild-type and neurotrophic gene mutant mice. J. Neurochem. 72(5):1930–1938.

    PubMed  CAS  Google Scholar 

  • Koliatsos, V. E., Clatterbuck, R. E., Winslow, J. W., Cayouette, M. H., and Price, D. L. (1993). Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. Neuron. 10:359–367.

    PubMed  CAS  Google Scholar 

  • Korte, M., Carroll, P., Wolf, E., Brem, G., Thoenen, H., and Bonhoeffer, T. (1995). Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA 92:8856–8860.

    PubMed  CAS  Google Scholar 

  • Lewin, G. R., and Barde, Y. A. (1996). Physiology of neurotrophins. Annu. Rev. Neurosci. 19:289–317.

    PubMed  CAS  Google Scholar 

  • Licinio, J., and Wong, M.-L. (2002). Brain-derived neurotrophic factor (BDNF) in stress and affective disorders (Editorial). Mol. Psychiatry 7:519.

    PubMed  CAS  Google Scholar 

  • Linnarsson, S., Bjorklund, A., and Ernfors, P. (1997). Learning deficit in BDNF mutant mice. Eur. J. Neurosci. 9:2581–2587.

    PubMed  CAS  Google Scholar 

  • Lister, R. G. (1987). The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185.

    PubMed  CAS  Google Scholar 

  • Liu, Y., Fowler, C. D., Young, L. J., Yan, Q., Insel, T. R., and Wang, Z. (2001). Expression and estrogen regulation of brain-derived neurotrophic factor gene and protein in the forebrain of female prairie voles. J. Comp. Neurol. 433:499–514.

    PubMed  CAS  Google Scholar 

  • Lohoff, F. W., Sander, T., Ferraro, T. N., Dahl, J. P., Gallinat, J., and Berrettini, W. H. (2005). Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am. J. Med. Genet. B 139B:51–53.

    CAS  Google Scholar 

  • Loudes, C., Petit, F., Kordon, C., and Faivre-Bauman, A. (2000). Brain-derived neurotrophic factor but not neurotrophin-3 enhances differentiation of somatostain neurons in hypothalamus cultures. Neuroendocrinology 72:144–153.

    PubMed  CAS  Google Scholar 

  • Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275.

    PubMed  CAS  Google Scholar 

  • Luine, V. N. (1997). Steroid hormone modulation of hippocampal-dependent spatial memory. Stress 2:21–36.

    PubMed  CAS  Article  Google Scholar 

  • Lyon, M. F., and Searle, A. G. (eds.) (1989). Genetic Variant and Strains of the Laboratory Mouse, 2nd edn., Oxford University Press, Oxford.

    Google Scholar 

  • Lyons, W. E., Mamounas, L. A., Ricaurt, G. A., Coppola, V., Reid, S. W., Bora, S. H., Wihler, C., Koliatsos, V. E., and Tessarollo, L. (1999). Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in connection with brain serotonin abnormalities. Proc. Natl. Acad. Sci. USA 96:15239–15244.

    PubMed  CAS  Google Scholar 

  • MacQueen, G. M., and Ramakrishnan, K. (2001). Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavior analogues of anxiety, nociception, and depression. Behav. Neurosci. 115(5):1145–1153.

    PubMed  CAS  Google Scholar 

  • Malmberg, A. B. (1999). Model of nociception: Hot plate, tail flick, and formalin tests in rodents. In Current Protocols in Neuroscience, Wiley, New York, pp. 8.9.1–8.9.16.

    Google Scholar 

  • Mamounas, L. A., Altar, C. A., Blu, M. E., Kaplan, D. R., Tessarollo, L., and Lyons, W. E. (2000). BDNF promotes the regenerative sprouting, but not survival, of serotonergic axons in the adult rat brain. J. Neurosci. 20(2):771–782.

    PubMed  CAS  Google Scholar 

  • Mamounas, L. A., Blu, M. E., Siuciak, J. A., and Altar, C. A. (1995). Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J. Neurosci. 15:7929–7939.

    PubMed  CAS  Google Scholar 

  • Marmigere, F., Rage, F., Tapia-Arancibia, L., and Arancibia, S. (1998). Expression of mRNAs encoding BDNF and its receptors in adult rat hypothalamus. Neuroreport 9:1159–1163.

    PubMed  CAS  Google Scholar 

  • Marmigere, F., Choby, C., Rage, F., Richard, S., and Tapia-Arancibia, L. (2001). Rapid stimulatory effects of brain-derived neurotrophic factor and neurotrophin-3 on somatostatin release and intracellular calcium rise in primary hypothalamus cell cultures. Neuroendocrinology 74:43–54.

    PubMed  CAS  Google Scholar 

  • Maswood, S., Truitt, W., Hotema, M., Caldarol-Pastuszka, M., and Uphouse, L. (1999). Estrous cycle modulation of extracellular serotonin in mediobasal hypothalamus: Role of the serotonin transporter and terminal autoreceptors. Brain Res. 831:146–154.

    PubMed  CAS  Google Scholar 

  • Maswood S, Stewart G, Uphouse L. (1995). Gender and estrous cycle effects of the 5-HT1A agonist, 8-OH-DPAT, on hypothalamic serotonin. Pharmacol Biochem Behav. 51(4):804–813.

    Google Scholar 

  • Mathews, T. A., Fedele, D. E., Coppelli, F. M., Avila, A. M., Murphy, D. L., and Andrews, A. M. (2004). Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J. Neurosci. Methods 140:169–181.

    PubMed  CAS  Google Scholar 

  • McAllister, A. K., Katz, L. C., and Lo, D. C. (1999). Neurotrophins and synaptic plasticity. Annu. Rev. Neurosci. 22:295–318.

    PubMed  CAS  Google Scholar 

  • Mefford, I. N. (1981). Application of high performance liquid chromatography with electrochemical detection to neurochemical analysis: Measurement of catecholamines, serotonin, and metabolites in rat brain. J. Neurosci. Methods 3:207–224.

    PubMed  CAS  Google Scholar 

  • Miknyoczki, S. J., Lang, D., Huang, L., Klein-Szanto, A. J., Dionne, C. A., and Ruggieri, B. A. (1999). Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: Expression patterns and effects on in vitro invasive behavior. Int. J. Cancer 81:417–427.

    PubMed  CAS  Google Scholar 

  • Miller, D. B., and O’Callaghan, J. P. (2002). Neuroendocrine aspects of the response to stress. Metabolism 51(6 Suppl 1):5–10.

    PubMed  CAS  Google Scholar 

  • Minichiello, L., Korte, M., Wolfer, D., Kuhu, R., Unsicker, K., Cestari, V., Rossi-Arnaud, C., Lipp, H. P., Bonhoeffer, T., and Klein, R. (1999). Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24:401–414.

    PubMed  CAS  Google Scholar 

  • Miranda, R. C., Sohrabji, F., and Toran-Allerand, D. (1994). Interactions of estrogen with the neurotrophins and their receptors during neural development. Horm. Behav. 28:367–375.

    PubMed  CAS  Google Scholar 

  • Montanez, S., Anthony Owens, W., Gould, G. G., Murphy, D. L., and Daws, L. C. (2003). Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice. J. Neurochem. 86:210–219.

    PubMed  CAS  Google Scholar 

  • Mossner, R., Deniel, S., Albert, D., Heils, A., Okladnova, O., Schmitt, A., and Lesch, K.-P. (2000). Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF). Neurochem. Int. 36(3):197–202.

    PubMed  CAS  Google Scholar 

  • Murphy, D. L., Lerner, A., Rudnick, G., and Lesch, K. P. (2004). Serotonin transporter: Gene, genetic disorders, and pharmacogenetics. Mol. Interv. 4:109–123.

    PubMed  CAS  Google Scholar 

  • Murphy, D. L., Li Q, Engel S, Wichems C, Andrews A, Lesch K. P, Uhl G.(2001). Genetic perspectives on the serotonin transporter. Brain Res Bull. 56(5):487–94.

    Google Scholar 

  • Murphy, D. L., Uhl, G. R., Holmes, A., Ren-Patterson, R., Hall, F. S., Sora, I., Detera-Wadleigh, S., and Lesch, K.-P. (2003). Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic disorders. Gene. Brain Behav. 2:350–364.

    CAS  Google Scholar 

  • Nawa, H., Carnahan, J., and Gall, C. (1995). BDNF protein measured by novel enzyme immunoassay in normal brain and after seizure: Partial disagreement with mRNA levels. Eur. J. Neurosci. 7:1527–1535.

    PubMed  CAS  Google Scholar 

  • Nestler, E. J., Barrot, M., and Di Leone, R. J. (2002). Neurology of depression. Neuron 28:13–25.

    Google Scholar 

  • Neves-Pereira, M., Cheung, J. K., Pasdar, A., Zhang, F., Breen, G., Yates, G., Sinclair, M., Crombie, C., Walker, N., and Clair, D. M. St. (2005). BDNF gene is a risk factor for schizophrenia in Scottish population. Mol. Psychiatry 10:208–212.

    PubMed  CAS  Google Scholar 

  • Oppenheim, R. W., Yin, Q. W., Prevette, D., and Yan, Q. (1992). Brain-derived neurotrophic factor rescues developing avian motoneurons from cell death. Nature 360:755–757.

    PubMed  CAS  Google Scholar 

  • Pelleymounter, M. A., Cullen, M. J., and Wellman, C. L. (1995). Characteristics of BDNF-induced weight loss. Exp. Neurol. 131:229–238.

    PubMed  CAS  Google Scholar 

  • Pirvola, U., Ylikoski, J., Palgi, J., Lehtonen, E., Arumae, U., and Saarma, M. (1992). Brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the peripheral target fields of developing inner ear ganglia. Proc. Natl. Acad. Sci. USA 89:9915–9919.

    PubMed  CAS  Google Scholar 

  • Pozzo-Miller, L. D., Gottschalk, W., Zhang, L., McDermott, K., Du, J., Gopalakrishnan, R., Oho, C., Sheng, Z. H., and Lu, B. (1999). Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in hippocampus of BDNF knockout mice. J. Neurosci. 19(12):4972–4983.

    PubMed  CAS  Google Scholar 

  • Rage, F., Riteau, B., Alonso, G., and Tapia-Arancibia, L. (1999). Brain-derived neurotrophic factor and neurotropin-3 enhance somatostatin gene expression through a likely direct effect on hypothalamic somatostatin neurons. Endocrinology 140:909–916.

    PubMed  CAS  Google Scholar 

  • Ren-Patterson, R. F., Kim, D. K., Zheng, X., Sherrill, S., Huang, S. J., Tolliver, T., and Murphy, D. L. (2005). Serotonergic-like progenitor cells propagated from neural stem cells in vitro: Survival with SERT protein expression following implantation into brains of mice lacking SERT. FASEB J. 19(11):1537, 1539.

    Google Scholar 

  • Ren-Patterson, R. F., Lauren, W. C., Holmes, A., Sherrill, S., Huang, S.-J., Tolliver, T., Lesch, P. K., and Murphy, L. D. (2005). Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. J. Neurosci. Res. 79:756–771.

    PubMed  CAS  Google Scholar 

  • Rios, M., Fan, G., Fekete, C., Kelly, J., Bates, B., Kuehn, R., Lechan, R. M., and Jaenisch, R. (2001). Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15(10):1748–1757.

    PubMed  CAS  Google Scholar 

  • Rumajogee, P., Madeira, A., Verge, D., Hamon, M., and Miquel, M. C. (2002). Up-regulation of the neuronal serotonergic phenotype in vitro: BDNF and cAMP share TrkB-dependent mechanisms. J. Neurochem. 83(6):1525–1528.

    PubMed  CAS  Google Scholar 

  • Rumajogee, P., Verge, D., and Hanoun, N., et al. (2004). Adaption of the serotoninergic neuronal phenotype in the absence of 5-HT autoreceptors or the 5-HT transporter: Involvement of BDNF and camp. Eur. J. Neurosci. 19(4):937–944.

    PubMed  Google Scholar 

  • Rumajogee, P., Verge, D., and Darmon, M., et al. (2005). Rapid up-regulation of the neuronal serotoninergic phenotype by brain-derived neurotrophic factor and cyclic adenosine monophosphate: Relation with raphe astrocytes. J. Neurosci. Res. 81(4):481–487.

    PubMed  CAS  Google Scholar 

  • Sen, S., Nesse, R. M., Stoltenberg, S. F., Li, S., Gleiberman, L., Chakravarti, A., Weder, A. B., and Burmeister, M. (2003). A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28:397–401.

    PubMed  CAS  Google Scholar 

  • Shimizu, E., Hashimoto, K., Okimura, N., Koike, K., Komatsu, N., Kumakiri, C., Nakazato, M., Watanabe, H., Shinoda, N., Okada, S.-I., and Iyo, M. (2003). Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiatry 54:70–75.

    PubMed  CAS  Google Scholar 

  • Smith, M. A., Makino, S., Kim, S. Y., and Kvetnansky, R. (1995). Stress increases brain-derived neurotrophic factor messenger ribonucleic acid in the hypothalamus and pituitary. Endocrinology 136:3743–3750.

    PubMed  CAS  Google Scholar 

  • Siuciak, J. A., Altar, C. A., Wiegand, S. J., and Lindsay, R. M. (1994). Antinoceptive effect of brain-derived neurotrophic factor and neurotrophin-3. Brain Res. 633:326–330.

    PubMed  CAS  Google Scholar 

  • Siuciak, J. A., Boylan, C., Fritsche, M., Altar, C. A., and Lindsay, R. M. (1996). BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res. 710:11–20.

    PubMed  CAS  Google Scholar 

  • Siuciak, J. A., Lewis, D. R., Wiegand, S. J., and Lindsay, R. M. (1997). Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol. Biochem. Behav. 56:131–137.

    PubMed  CAS  Google Scholar 

  • Singh, M., Meyer, E. M., and Simpkins, J. W. (1995). The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats. Endocrinology 136:2320–2324.

    PubMed  CAS  Google Scholar 

  • Sklar, P., Gabriel, S. B., Mclnnis, M. G., Bennett, P., Lim, Y.-M., Tsan, G., Schaffner, S., Kiorov, G., Jones, I., Owen, M., Craddock, N., DePaulo, J. R., and Lander, E. S. (2002). Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol. Psychiatry 7:579–593.

    PubMed  CAS  Google Scholar 

  • Smith, S. S. (1994). Female sex steroid hormones: From receptors to networks to performance-actions on the sensorimotor system. Prog. Neurobiol. 44:55–86.

    PubMed  CAS  Google Scholar 

  • Solum, D. T., and Handa, R. J. (2002). Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J. Neurosci. 22(7):2650–2659.

    PubMed  CAS  Google Scholar 

  • Spenger, C., Hyman, C., Studer, L., Egli, M., Evatouchenko, L., Jackson, C., Dahl-Jorgensen, A., Lindsay, R. M., and Seiler, R. W. (1995). Effects of BDNF on dopaminergic, serotonergic, and GABA-ergic neurons in cultures of human fetal ventral mesencephalon. Exp. Neurol. 133(1):50–63.

    PubMed  CAS  Google Scholar 

  • Suter-Crazzolara, C. A., Lachmund, Arab, S. F., and Unsicker, K. (1996). Expression of neurotrophins and their receptors in the developing and adult rat adrenal gland. Brain Res. Mol. Brain Res. 43:351–355.

    PubMed  CAS  Google Scholar 

  • Tjurmina, O. A., Armando, I., Saavedra, J. M., Goldstein, D. S., and Murphy, D. L. (2000). Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology 143(12):4520–4526.

    Google Scholar 

  • Tjurmina, O. A., Armando, I., Saavedra, J. M., Li, Q., and Murphy, D. L. (2004). Life-long serotonin reuptake deficiency results in complex alterations in adrenomedullary responses to stress. Ann. NY Acad. Sci. 1018:99–104.

    PubMed  CAS  Google Scholar 

  • Tonra, J. R., Ono, M., and Liu, X. (1999). Brain-derived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS-Lepr(db)/lepr(db) mice. Diabetes 48:588–594.

    PubMed  CAS  Google Scholar 

  • Toran-Allerand, C. D., Singh, M., and Setalo, G., Jr. (1999). Novel mechanisms of estrogen action in the brain: New plays in an old story. Front. Neuroendocrinol. 20:97–121.

    PubMed  CAS  Google Scholar 

  • Torres, G. E., Gainetdinov, R. R., and Caron, M. G. (2003). Plasma membrane monoamine transporters: Structure, regulation and function. Nat. Rev. Neurosci. 4(1):13–25.

    PubMed  CAS  Google Scholar 

  • Vitalis, T., Cases, O., Gillies, K., Hanoun, N., Hamon, M., Seif, I., Gaspar, P., Kind, P., and Price, D. J. (2002). Interactions between TrkB signaling and serotonin excess in the developing murine somatosensory cortex: A role in tangential and radial organization of thalamocortical axons. J. Neurosci. 22(12):4987–5000.

    PubMed  CAS  Google Scholar 

  • Vogel, C., Mossner, R., Gerlach, M., Heinemann, T., Murphy, D. L., Riederer, P., Lesch, K.-P., and Sommer, C. (2003). Absence of thermal hyperalgesia in serotonin transporter-deficient mice. J. Neurosci. 23(2):708–715.

    PubMed  CAS  Google Scholar 

  • Wichems, C. H., Li, Q., Holmes, A., Crawley, J. N., Tjurmina, O., Goldstein, D., Andrews, A. M., Lesch, K.-P., and Murphy, D. L. (2000). Mechanisms mediating the increased anxiety-like behavior and excessive responses to stress in mice lacking the serotonin transporter. Soc. Neurosci. Abstr. 26:400.

    Google Scholar 

  • Xu, B., Zang, K., Ruff, N. L., Zhang, Y. A., McConnel, S. K., Stryker, M. P., and Reichardt, L. F. (2000). Cortical degeneration in the absence of neurotrophin signaling: Dendritic retraction and neuronal loss after removal of the receptor TrkB. Neuron 26:233–245.

    PubMed  CAS  Google Scholar 

  • Yamada, K., Mizuno, M., and Nabeshima, T. (2002). Role for brain-derived neurotrophic factor in learning and memory. Life Sci. 70:735–744.

    PubMed  CAS  Google Scholar 

  • Yan, Q., Elliott, J., and Snider, W. D. (1992). Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 360:753–755.

    PubMed  CAS  Google Scholar 

  • Yan, Q., Radeke, M. J., Matheson, C. R., Talvenheimo, J., Welcher, A. A., and Feinstein, S. C. (1997). Immunocytochemical localization of TrkB in the central nervous system of the adult. J. Comp. Neurol. 382:546–547.

    Google Scholar 

  • Young, A. H., Dow, R. C., Goodwin, G. M., and Fink, G. (1993). The effects of adrenalectomy and ovariectomy on the behavioral and hypothermic responses of rats to 8-hydroxy-2(DI-n-propylamino) tetralin (8-OH-DPAT). Neuropharmacology 32:653–657.

    PubMed  CAS  Google Scholar 

  • Zelena, D., Mergl, Z., Foldes, A., Kovacs, K. J., Toth, Z., and Makara, G. B. (2003). Role of hypothalamic inputs in maintaining pituitary–adrenal responsiveness in repeated restraint. Am. J. Physiol. Endocrinol. Metab. 285(5):E1110–E1117.

    PubMed  CAS  Google Scholar 

  • Zhou, J., and Lacovitti, L. (2000). Mechanism governing the differentiation of a serotonergic phenotype in culture. Brain Res. 877(1):37–46.

    PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

This research was supported by the National Institute of Mental Health Intramural Research Program. We thank Suzanne Sherrill, Teresa Tolliver and Su-Jan Huang for their assistance with the experiments.

Author information

Affiliations

  1. Laboratory of Clinical Science, NIMH, Bethesda, MD, USA

    Renee F. Ren-Patterson, Lauren W. Cochran & Dennis L. Murphy

  2. Section on Behavioral Genomics, NIAAA, Bethesda, MD, USA

    Andrew Holmes

  3. Psychiatry and Psychotherapy, University of Wurzburg, Wurzburg, Germany

    Klaus-Peter Lesch

  4. Laboratory of Development Neurobiology, NICHD, Rockville, MD, USA

    Bai Lu

  5. Laboratory of Clinical Science, National Institute of Mental Health, Building 10, Room 3D41, Bethesda, 20892-1264, MD, USA

    Dennis L. Murphy

Authors
  1. Renee F. Ren-Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lauren W. Cochran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Klaus-Peter Lesch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bai Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dennis L. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dennis L. Murphy.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ren-Patterson, R.F., Cochran, L.W., Holmes, A. et al. Gender-Dependent Modulation of Brain Monoamines and Anxiety-like Behaviors in Mice with Genetic Serotonin Transporter and BDNF Deficiencies. Cell Mol Neurobiol 26, 753–778 (2006). https://doi.org/10.1007/s10571-006-9048-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-006-9048-6

KEY WORDS:

  • neurotrophins
  • serotonin
  • knockout
  • gene interaction
  • estrogen
  • TrkB
  • dopamine