Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-29T00:45:42.401Z Has data issue: false hasContentIssue false
  • English
  • Français

New Lessons From Knockout Mice: The Role of Serotonin During Development and Its Possible Contribution to the Origins of Neuropsychiatric Disorders

Published online by Cambridge University Press:  07 November 2014

Jay A. Gingrich ,
Mark S. Ansorge ,
Robert Merker ,
Noelia Weisstaub  and
Mingming Zhou
Get access Rights & Permissions [Opens in a new window]

Abstract

Serotonin (5-HT) modulates numerous processes in the central nervous system that are relevant to neuropsychiatric function and dysfunction. It exerts significant effects on anxiety, mood, impulsivity, sleep, ingestive behaviors, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several neuropsychiatric conditions but efforts to more clearly understand the mechanisms of this influence have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of 5-HT as well as several enzymes that control its synthesis and metabolism. Pharmacologic agents that target specific receptors have provided clues regarding the function of these receptors in the adult brain. 5-HT is also an important modulator of neural development and several groups have employed a genetic strategy to ablate specific components of the 5-HT system in order to understand the role of different serotonergic in development of brain systems relevant to behavior. Several inactivation mutations of specific 5-HT receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases, knockout mice have been used to confirm what has already been suspected based on pharmacologic studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior.

Type
Review Article
Information
CNS Spectrums , Volume 8 , Issue 8: Genetically Altered Mice in the Study of Neuropsychiatrty , August 2003 , pp. 572 - 577
Copyright
Copyright © Cambridge University Press 2003

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1.Brunner, HG, Nelen, M, Breakefield, XO, Ropers, HH, van Oost, BA. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science. 1993;262:578–580.CrossRefGoogle ScholarPubMed
2.Caspi, A, McClay, J, Moffitt, TE, et al.Role of genotype in the cycle of violence in maltreated children. Science. 2002;297:851–854.CrossRefGoogle ScholarPubMed
3.Hamer, D. Genetics. Rethinking behavior genetics. Science. 2002;298:71–72.CrossRefGoogle ScholarPubMed
4.Lesch, KP, Bengel, D, Heils, A, et al.Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996;274:1527–1531.CrossRefGoogle ScholarPubMed
5.Bellivier, F, Szoke, A, Henry, C, et al.Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders. Biol Psychiatry. 2000;48:319–322.CrossRefGoogle ScholarPubMed
6.Joiner, TE Jr., Johnson, F, Soderstrom, K. Association between serotonin transporter gene polymorphism and family history of attempted and completed suicide. Suicide Life Threat Behav. 2002;32:329–332.CrossRefGoogle ScholarPubMed
7.Baca-Garcia, E, Vaquero, C, Diaz-Sastre, C, Saiz-Ruiz, J, Fernandez-Piqueras, J, de Leon, J. A gender-specific association between the serotonin transporter gene and suicide attempts. Neuropsychopharmacology. 2002;26:692–695.CrossRefGoogle ScholarPubMed
8.Courtet, P, Baud, P, Abbar, M, et al.Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene. Mol Psychiatry. 2001;6:338–341.CrossRefGoogle ScholarPubMed
9.Mann, JJ, Huang, YY, Underwood, MD, et al.A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry. 2000;57:729–738.CrossRefGoogle ScholarPubMed
10.Du, L, Faludi, G, Palkovits, M, et al.Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims. Biol Psychiatry. 1999;46:196–201.CrossRefGoogle ScholarPubMed
11.Hariri, AR, Mattay, VS, Tessitore, A, et al.Serotonin transporter genetic variation and the response of the human amygdala. Science. 2002;297:400–403.CrossRefGoogle ScholarPubMed
12.Murphy, DL, Wichems, C, Li, Q, Heils, A. Molecular manipulations as tools for enhancing our understanding of 5-HT neurotransmission. Trends Pharmacol Sci. 1999;20:246–252.CrossRefGoogle ScholarPubMed
13.Murphy, DL, Li, Q, Engel, S, et al.Genetic perspectives on the serotonin transporter. Brain Res Bull. 2001;56:487–494.CrossRefGoogle ScholarPubMed
14.Bonasera, SJ, Tecott, LH. Mouse models of serotonin receptor function: toward a genetic dissection of serotonin systems. Pharmacol Ther. 2000;88:133–142.CrossRefGoogle Scholar
15.Gingrich, JA, Hen, R. Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology (Berl). 2001;155:1–10.CrossRefGoogle ScholarPubMed
16.Gingrich, JA. Mutational analysis of the serotonergic system: recent findings using knockout mice. Curr Drug Target CNS Neurol Disord. 2002;1:449–465.CrossRefGoogle ScholarPubMed
17.Zhuang, X, Gross, C, Santarelli, L, Compan, V, Trillat, AC, Hen, R. Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors. Neuropsychopharmacology. 1999;21:52S–60S.CrossRefGoogle ScholarPubMed
18.Ramboz, S, Oosting, R, Amara, DA, et al.Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc Natl Acad Sci U S A. 1998;95:14476–14481.CrossRefGoogle ScholarPubMed
19.Parks, CL, Robinson, PS, Sibille, E, Shenk, T, Toth, M. Increased anxiety of mice lacking the serotonin 1A receptor. Proc Natl Acad Sci U S A. 1998;95:10734–10739.CrossRefGoogle Scholar
20.Heisler, LK, Chu, HM, Brennan, TJ, et al.Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci U S A. 1998;95:15049–15054.CrossRefGoogle ScholarPubMed
21.Richer, M, Hen, R, Blier, P. Modification of serotonin neuron properties in mice lacking 5-HT1A receptors. Eur J Pharmacol. 2002;435:195–203.CrossRefGoogle Scholar
22.Sibille, E, Pavlides, C, Benke, D, Toth, M. Genetic inactivation of the serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. J Neurosci. 2000;20:2758–2765.CrossRefGoogle Scholar
23.Santarelli, L, Gross, C, Monckton, J, et al. The 5-HT1A receptor is required for the effect of chronic fluoxetine on behavior and neurogenesis. Paper presented at: Annual Meeting of theSociety for Neuroscience; November 10-15, 2001; San Diego, Calif.Google Scholar
24.Gross, C, Zhuang, X, Stark, KL, et al.Serotoninl A receptor acts during development to establish normal anxiety-like behavior in the adult. Nature. 2002;416:396–400.CrossRefGoogle Scholar
25.Kelley, SP, Bratt, AM, Hodge, CW. Targeted gene deletion of the 5-HT(3A) receptor subunit produces an anxiolytic phenotype in mice. Eur J Pharmacol. 2003;461:19–25.CrossRefGoogle ScholarPubMed
26.Zhang, ZJ, Schmidt, DE, de Paulis, T, et al.Anxiolytic-like effects of DAIZAC, a selective high-affinity 5-HT(3) receptor antagonist, in the mouse elevated plusmaze. Pharmacol Biochem Behav. 2001;69:571–578.CrossRefGoogle ScholarPubMed
27.Holmes, A, Yang, RJ, Murphy, DL, Crawley, JN. Abnormal emotional behaviors and age related obesity in 5-HT transporter defficient mice. Abstract presented at: Annual Meeting of the Society of Neuroscience; November 10-15, 2001; San Diego, Calif.Google Scholar
28.Kent, JM, Coplan, JD, Gorman, JM. Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety. Biol Psychiatry. 1998;44:812–824.CrossRefGoogle ScholarPubMed
29.Pfaar, H, von Holst, A, Vogt Weisenhorn, DM, Brodski, C, Guimera, J, Wurst, W. mPet-1, a mouse ETS-domain transcription factor, is expressed in central serotonergic neurons. Dev Genes Evol. 2002;212:43–46.CrossRefGoogle ScholarPubMed
30.Hendricks, TJ, Fyodorov, DV, Wegman, LJ, et al.Pet-1 ETS Gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior. Neuron. 2003;37:233–247.CrossRefGoogle Scholar
31.Lucki, I, Dalvi, A, Mayorga, AJ. Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. Psychopharmacology (Berl). 2001;155:315–322.CrossRefGoogle Scholar
32.Liu, X, Gershenfeld, HK. Genetic differences in the tail-suspension test and its relationship to imipramine response among 11 inbred strains of mice. Biol Psychiatry. 2001;49:575–581.CrossRefGoogle ScholarPubMed
33.Mayorga, AJ, Dalvi, A, Page, ME, Zimov-Levinson, S, Hen, R, Lucki, I. Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice. J Pharmacol Exp Ther. 2001;298:1101–1107.Google ScholarPubMed
34.Artigas, F, Celada, P, Laruelle, M, Adell, A. How does pindolol improve antidepressant action? Trends Pharmacol Sci. 2001;22:224–228.CrossRefGoogle ScholarPubMed
35.Parsons, LH, Kerr, TM, Tecott, LH. 5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission. J Neurochem. 2001;77:607–617.CrossRefGoogle Scholar
36.Malagie, I, Trillat, AC, Bourin, M, Jacquot, C, Hen, R, Gardier, AM. 5-HT1B autoreceptors limit the effects of selective serotonin re-uptake inhibitors in mouse hippocampus and frontal cortex. J Neurochem. 2001;76:865–871.CrossRefGoogle ScholarPubMed
37.de Groote, L, Olivier, B, Westenberg, HG. Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT(1B) autoreceptors: a microdialysis study in knockout mice. Psychopharmacology (Berl). 2002;162:419–424.CrossRefGoogle ScholarPubMed
38.Holmes, A, Yang, RJ, Murphy, DL, Crawley, JN. Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology. 2002;27:914–923.CrossRefGoogle ScholarPubMed
39.Lira, A, Zhou, M, Castanon, N, et al.Altered dorsal raphé function and depression-related behaviors in serotonin transporter deficient mice. Biol. Psychiatry. In press.Google Scholar
40.Vogel, G, Neill, D, Hagler, M, Kors, D, Hartley, P. Decreased intracranial self-stimulation in a new animal model of endogenous depression. Neurosci Biobehav Rev. 1990;14:65–68.CrossRefGoogle Scholar
41.Hansen, HH, Mikkelsen, JD. Long-term effects on serotonin transporter mRNA expression of chronic neonatal exposure to a serotonin reuptake inhibitor. Eur J Pharmacol. 1998;352:307–315.CrossRefGoogle ScholarPubMed
42.Mann, JJ, Brent, DA, Arango, V. The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system. Neuropsychopharmacology. 2001;24:467–477.CrossRefGoogle ScholarPubMed
43.Virkkunen, M, Linnoila, M. Brain serotonin, type II alcoholism and impulsive violence. J Stud Alcohol Suppl. 1993;11:163–169.CrossRefGoogle ScholarPubMed
44.Ibanez, A, Blanco, C, de Castro, IP, Fernandez-Piqueras, J, Saiz-Ruiz, J. Genetics of pathological gambling. J Gambl Stud. 2003;19:11–22.CrossRefGoogle ScholarPubMed
45.Cases, O, Seif, I, Grimsby, J, et al.Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science. 1995;268:1763–1766.CrossRefGoogle ScholarPubMed
46.Cases, O, Vitalis, T, Seif, I, De Maeyer, E, Sotelo, C, Gaspar, P. Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron. 1996;16:297–307.CrossRefGoogle ScholarPubMed
47.Olivier, B, Mos, J, van Oorschot, R, Hen, R. Serotonin receptors and animal models of aggressive behavior. Pharmacopsychiatry. 1995;28(suppl 2):80–90.CrossRefGoogle ScholarPubMed
48.Saudou, F, Amara, DA, Dierich, A, et al.Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science. 1994;265:1875–1878.CrossRefGoogle Scholar
49.Ramboz, S, Saudou, F, Amara, DA, et al.5-HT1B receptor knock out-behavioral consequences. Behav Brain Res. 1996;73:305–312.CrossRefGoogle ScholarPubMed
50.Ramboz, S, Saudou, F, Amara, DA, et al.Behavioral characterization of mice lacking the 5-HT1B receptor. NIDA Res Monogr. 1996;161:39–57.Google Scholar
51.Holmes, A, Murphy, DL, Crawley, JN. Reduced aggression in mice lacking the serotonin transporter. Psychopharmacology (Berl). 2002;161:160–167.CrossRefGoogle ScholarPubMed
52.Andrews, AM, Wichems, C, Li, Q, Heils, A, Lesch, K, Murphy, D. A microdialysis study of the effects of high K+ and paroxetine on extracellular serotonin concentrations in serotonin transporter knock-out mice. Paper presented at: Annual Meeting of the Society of Neuroscience; November 7-12, 1998; Los Angeles, Calif.Google Scholar
53.Fabre, V, Beaufour, C, Evrard, A, et al.Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci. 2000;12:2299–2310.CrossRefGoogle Scholar
54.Rocha, BA, Scearce-Levie, K, Lucas, JJ, et al.Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor. Nature. 1998;393:175–178.CrossRefGoogle ScholarPubMed
55.Castanon, N, Scearce-Levie, K, Lucas, JJ, Rocha, B, Hen, R. Modulation of the effects of cocaine by 5-HT1B receptors: a comparison of knockouts and antagonists. Pharmacol Biochem Behav. 2000;67:559–566.CrossRefGoogle Scholar
56.Nye, HE, Nestler, EJ. Induction of chronic Fos-related antigens in rat brain by chronic morphine administration. Mol Pharmacol. 1996;49:636–645.Google ScholarPubMed
57.Akiyama, K, Ishihara, T, Kashihara, K. Effect of acute and chronic administration of methamphetamine on activator protein-1 binding activities in the rat brain regions. Ann N Y Acad Sci. 1996;801:13–28.CrossRefGoogle ScholarPubMed
58.Bachtell, RK, Wang, YM, Freeman, P, Risinger, FO, Ryabinin, AE. Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors. Brain Res. 1999;847:157–165.CrossRefGoogle ScholarPubMed
59.Scearce-Levie, K, Chen, JP, Gardner, E, Hen, R. 5-HT receptor knockout mice: pharmacological tools or models of psychiatric disorders. Ann N Y Acad Sci. 1999;868:701–715.CrossRefGoogle ScholarPubMed
60.Vitalis, T, Cases, O, Callebert, J, et al.Effects of monoamine oxidase A inhibition on barrel formation in the mouse somatosensory cortex: determination of a sensitive developmental period. J Comp Neurol. 1998;393:169–184.3.0.CO;2-0>CrossRefGoogle ScholarPubMed
61.Upton, AL, Ravary, A, Salichon, N, et al.Lack of 5-HT(1B) receptor and of serotonin transporter have different effects on the segregation of retinal axons in the lateral geniculate nucleus compared to the superior colliculus. Neuroscience. 2002;111:597–610.CrossRefGoogle Scholar
62.Gingrich, JA, Hen, R. The broken mouse: the role of development, plasticity and environment in the interpretation of phenotypic changes in knockout mice. Curr Opin Neurobiol. 2000;10:146–152.CrossRefGoogle ScholarPubMed