Skip to main content
SpringerLink
Log in

Knockout and Mutant Rats

  • Protocol
  • First Online:
Transgenic and Mutant Tools to Model Brain Disorders

Part of the book series: Neuromethods ((NM,volume 44))

  • 691 Accesses

Abstract

Rats have been extensively used to explore the brain mechanisms underlying psychiatric disorders. However, due to a lack of sufficient tools for the generation of knockout or mutant rats, there has been a general lag in the understanding of genetic factors in psychiatric and neurodevelopmental disorders, compared to other popular experimental animal models. Recently, several mutant and knockout rats have been generated using N-ethyl-N-nitrosourea (ENU)-driven target selected mutagenesis. Two of them, the serotonin transporter knockout (SERT−/−) rat and the dopamine D1 receptor mutant (DRD1−/−) rat, are described in relation to four important (neurodevelopmental) psychiatric disorders: depression, autism, schizophrenia and drug addiction. It has been shown that the SERT−/− rats display increased stress-sensitivity, reduced social approach, reduced impulsivity, and increased cocaine self-administration, but no change in sensorimotor integration has been found. These characteristics could potentially make the SERT−/− rat extremely valuable to improv the understanding of mechanisms underlying depression, autism and drug addiction. Furthermore, preliminary data show that the DRD1−/− rat shows alterations in locomotor activity, is less responsive to psychostimulants, displays deficits in working memory, and may be impaired in sensorimotor integration. These data argue that the DRD1−/− rat models symptoms of schizophrenia as well as drug addiction. Experiments are underway to identify the underlying neuronal mechanisms. Collectively, these findings illustrate that knockout and mutant rats are very valuable in modeling human psychiatric disorders. Furthermore, exploitation of the rat’s advantages in measuring complex cognitive functions will complement mouse knockout studies. In the future, research using knockout and mutant rats is expected to reveal the novel targets in the treatment of psychiatric disorders, to be very helpful in the development of new therapies and the identification of risk groups based on genetic background.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

     SmithKline Beecham Pharmaceuticals, Harwell, MRC Mouse Genome Centre and Mammalian Genetics Unit, Imperial College School of Medicine at St Mary’s, Royal London Hospital, St Bartholomew’s and the Royal London School of Medicine, Phenotype Assessment.

References

  1. Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and congnitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28:771-784

    Article  CAS  PubMed  Google Scholar 

  2. Stemple DL (2004) TILLING - a high-throughput harvest for functional genomics. Nat Rev Genet 5(2):145-150

    Article  CAS  PubMed  Google Scholar 

  3. Noveroske JK, Weber JS, Justice MJ (2000) The mutagenic action of N-ethyl-N-nitrosourea in the mouse. Mamm Genome 11(7):478-483

    Article  CAS  PubMed  Google Scholar 

  4. Jansen G, Hazendonk E, Thijssen KL et al (1997) Reverse genetics by chemical mutagenesis in Caenorhabditis elegans. Nat Genet 17:119-121

    Article  CAS  PubMed  Google Scholar 

  5. Bentley A, MacLennan B, Calvo J et al (2000) Targeted recovery of mutations in drosophila. Genetics 156:1169-1173

    CAS  PubMed  Google Scholar 

  6. Wienholds E, Schulte-Merker S, Waldericht B et al (2002) Target-selected inactivation of the zebrafish rag1 gene. Science 297:99-102

    Article  CAS  PubMed  Google Scholar 

  7. McCallum CM, Comai L, Greene EA et al (2000) Targeted screening for induced mutations. Nat Biotechnol 18:455-457

    Article  CAS  PubMed  Google Scholar 

  8. Till BJ, Reynolds SH, Weil C et al (2004) Discovery of induced point mutations in maize genes by TILLING. BMC Plant Biol 28:4-12

    Google Scholar 

  9. Perry JA, Wang TL, Welham TJ et al (2003) A TILLING reverse genetics tool and a web-accessible collection of mutants of the legume Lotus japonicus. Plant Physiol 131:866-871

    Article  CAS  PubMed  Google Scholar 

  10. Zan Y, Haag JD, Chen KS et al (2003) Production of knockout rats using ENU mutagenesis and a yeast-based screening assay. Nat Biotechnol 21(6):645-651

    Article  CAS  PubMed  Google Scholar 

  11. Smits BM, Mudde JB, Plasterk RH et al (2004) Target-selected mutagenesis of the rat. Genomics 83(2):332-334

    Article  CAS  PubMed  Google Scholar 

  12. Smits BM, Mudde JB, van de Belt J et al (2006) Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis. Pharmacogenet Genomics 16(3):159-169

    CAS  PubMed  Google Scholar 

  13. Amos-Landgraf JM, Kwong LN, Kendziorski CM et al (2007) A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci USA 104(10):4036-4041

    Article  CAS  PubMed  Google Scholar 

  14. Homberg JR, Olivier JDA, Smits BMG et al (2007) Characterization of the serotonin transporter knockout rat: A selective change in the functioning of the serotonergic system. Neuroscience 146:1662-1676

    Article  CAS  PubMed  Google Scholar 

  15. van Boxtel R, Toonen PW, van Roekel H et al (2008) Lack of DNA mismatch repair protein MSH6 in the rat results in hereditary non-polyposis colorectal cancer-like tumorigenesis. Carcinogenesis 29(6):1290-1297

    Article  PubMed  Google Scholar 

  16. Baker KE, Parker R (2004) Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr Opin Cell Biol 16:293-299

    Article  CAS  PubMed  Google Scholar 

  17. Takada A, Curzon G (1995) Presynaptic regulation of extracellular serotonin concentration in brain. In: Wong DT, Bymaster FP, Engleman EA (eds) Serotonin in the central nervous system and periphery, 7th edn. Elsevier Science B.V., Oxford, England, p 3

    Google Scholar 

  18. Murphy DL, Andrews AM, Wichems CH et al (1998) Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems and consequent implications for understanding the action of serotonergic drugs. J Clin Psychiatry 59(Suppl 15):4-12

    CAS  PubMed  Google Scholar 

  19. Homberg JR, Pattij T, Janssen MCW et al (2007) Serotonin transporter deficiency in rats improves inhibitory control but not behavioral flexibility. Eur J Neurosci 26(7):2066-2073

    Article  PubMed  Google Scholar 

  20. Rogers DC, Fisher EM, Brown SD et al (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 8:711-713

    Article  CAS  PubMed  Google Scholar 

  21. Kravitz EA (2000) Serotonin and aggression: Insights gained from a lobster model system and speculations on the role of amine neurons in a complex behavior. J Comp Phyiol [A] 186:221-238

    Article  CAS  Google Scholar 

  22. Ursin R (2000) Serotonin and sleep. Sleep Med Rev 6:55-69

    Article  Google Scholar 

  23. Richards KS, Simon DJ, Pulver SR et al (2003) Serotonin in the developing stomatogastric system of the lobster, Homarus americanus. J Neurobiol 54:380-392

    Article  CAS  PubMed  Google Scholar 

  24. Graeff FG, Guimaraes FS, De Andrade TG et al (1996) Role of 5-HT in stress, anxiety and depression. Pharmacol Biochem Behav 54:129-141

    Article  CAS  PubMed  Google Scholar 

  25. Hull EM, Lorrain DS, Du J, Matuszewich L et al (1999) Hormone-neurotransmitter interactions in the control of sexual behavior. Behav Brain Res 205:105-116

    Article  Google Scholar 

  26. Evenden JL (1999) Varieties of impulsivity. Psychopharmacology 146:348-361

    Article  CAS  PubMed  Google Scholar 

  27. Olivier B (2004) Serotonin and aggression. Ann NY Acad Sci 1036:382-392

    Article  CAS  PubMed  Google Scholar 

  28. Linnoila M, Virkkunen M, Scheinin M et al (1983) Low cerebrospinal-fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from non-impulsive violent behavior. Life Sci 33:2609-2614

    Article  CAS  PubMed  Google Scholar 

  29. LeMarquand DG, Pihl RO, Young SN et al (1998) Tryptophan depletion, executive functions and disinhibition in aggressive, adolescent males. Neuropsychopharmacol 19:333-341

    CAS  Google Scholar 

  30. Fuller RW (1997) The influence of fluoxetine on aggressive behavior. Neuropsy­cho­phar­macol 16:373-374

    Article  Google Scholar 

  31. Brady KT, Myrick H, McElroy S (1998) The relationship between substance use disorders, impulse control disorders and pathological aggression. Am J Addict 7:221-230

    PubMed  Google Scholar 

  32. Cherek DR, Lane SD (2000) Fenfluramine effects on impulsivity in a sample of adults with and without history of conduct disorder. Psychopharmacol 152:149-156

    Article  CAS  Google Scholar 

  33. Clark L, Roiser JP, Cools R et al (2005) Stop signal response inhibition is not modulated by tryptophan depletion or the serotonin transporter polymorphism in healthy volunteers:implications for the 5-HT theory of impulsivity. Psychopharmacol 182:570-578

    Article  CAS  Google Scholar 

  34. Cools R, Blackwell A, Clark L et al (2005) Tryptophan depletion disrupts the motivational guidance of goaldirected behavior as a function of trait impulsivity. Neuropsychopharmacol 30:1362-1373

    CAS  Google Scholar 

  35. Watson KK, Ghodasra JH, Platt ML (2009) Serotonin transporter genotype modulates social reward and punishment in rhesus macaques. PLoS ONE 4(1):e4156

    Article  PubMed  Google Scholar 

  36. Clarke HF, Dalley JW, Crofts HS et al (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science 304:878-880

    Article  CAS  PubMed  Google Scholar 

  37. Fox MA, Andrews AM, Wendland JR et al (2007) A pharmacological analysis of mice with a targeted disruption of the serotonin transporter. Psychopharmacol 195(2):147-166

    Article  CAS  Google Scholar 

  38. Brune CW, Kim SJ, Salt J et al (2006) 5-HTTLPR Genotype-specific phenotype in children and adolescents with autism. Am J Psychiatry 163(12):2148-2156

    Article  PubMed  Google Scholar 

  39. Coppen A, Eccleston E, Craft I et al (1973) Letter: Total and free plasma-tryptophan concentration and oral contraception. Lancet 2:1498

    Article  CAS  PubMed  Google Scholar 

  40. Cowen PJ, Parry-Billings M, Newsholme EA (1989) Decreased plasma tryptophan levels in major depression. J Affect Disord 16:27-31

    Article  CAS  PubMed  Google Scholar 

  41. Asberg M, Thorén P, Träskman L et al (1976) “Serotonin depression” - a biochemical subgroup within the affective disorders? Science 191:478-480

    Article  CAS  PubMed  Google Scholar 

  42. Owens MJ, Nemeroff CB (1998) The serotonin transporter and depression. Depress Anxiety 8:5-12

    Article  PubMed  Google Scholar 

  43. Olivier JDA, van der Hart MGC, van Swelm RPL et al (2008) A study in male and female serotonin transporter knockout rats: An animal model for anxiety and depression disorders. Neuroscience 152(3):573-584

    Article  CAS  PubMed  Google Scholar 

  44. Saykin AJ, Shtasel D, Gur RE et al (1994) Neuropsychological deficits in neuroleptic naïve patients with first-episode schizophrenia. Arch Gen Psychiatry 51:124-131

    CAS  PubMed  Google Scholar 

  45. Geyer MA, Braff DL (1982) Habituation of the blink reflex in normal and schizophrenic patients. Psychophysiol 19:1-6

    Article  CAS  Google Scholar 

  46. Cadenhead KS, Geyer MA, Braff DL (1993) Impaired startle prepulse inhibition and habituation in schizotypal patients. Am J Psychiatry 150:1862-1867

    CAS  PubMed  Google Scholar 

  47. Olivier JD, Jans LA, Korte-Bouws GA, Korte SM, Deen PM, Cools AR, Ellenbroek BA, Blokland A (2008) Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knoctout rats. Psychopharmacology (Berl), 200(2): 243-254

    Google Scholar 

  48. Uhl GR, Grow RW (2004) The burden of complex genetics in brain disorders. Arch Gen Psychiatry 61:223-229

    Article  PubMed  Google Scholar 

  49. Mannelli P, Patkar AA, Peindl K et al (2006) Polymorphism in the serotonin transporter gene and moderators of prolactin response to metachlorophenylpiperazine in African-American cocaine abusers and controls. Psychiatry Res 144:99-108

    Article  CAS  PubMed  Google Scholar 

  50. Gerra G, Zaivovic A, Garofano L et al (2007) Perceived parenting behaviour in the childhood of cocaine users: relationship with genotype and personality traits. Am J Med Genet B Neuropsychiatr Genet 144:52-57

    Google Scholar 

  51. Homberg JR, De Boer SF, Raaso HS et al (2008) Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats. Psychopharmacology (Berl) 200(3):367-380

    Article  CAS  Google Scholar 

  52. David SP, Murthy NV, Rabiner EA et al (2005) A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 25:2586-2590

    Article  CAS  PubMed  Google Scholar 

  53. Lesch KP, Gutknecht L (2005) Pharmacogentics of the serotonin transporter. Prog Neuropsychopharmacol Biol Psychiatry 29:1062-1073

    Article  CAS  PubMed  Google Scholar 

  54. Mann JJ, Huang YY, Underwood MD et al (2000) Serotonin transporter gene promoter polymorphism. (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 57:729-738

    Article  CAS  PubMed  Google Scholar 

  55. Caspi A, Sugden K, Moffitt TE et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631):291-293

    Article  Google Scholar 

  56. Alfimova MV, Golimbet VE, Korovaitseva GI et al (2008) The modulatory influence of polymorphism of the serotonin transporter gene on characteristics of mental maladaptation in relatives of patients with endogenous psychoses. Neurosci Behav Physiol 38(3):253-258

    Article  CAS  PubMed  Google Scholar 

  57. Drago J, Gerfen CR, Lachowicz JE et al (1994) Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc Natl Acad Sci USA 91(26):12564-12568

    Article  CAS  PubMed  Google Scholar 

  58. Drago J, Gerfen CR, Westphal H et al (1996) D1 dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum. Neuroscience 74(3):813-823

    Article  CAS  PubMed  Google Scholar 

  59. Xu M (2007) Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice. J Neurosci 27(48):13140-13150

    Article  PubMed  Google Scholar 

  60. Al-Fulaij MA, Ren Y, Beinborn M et al (2008) Pharmacological analysis of human D1 and D2 dopamine receptor missense variants. J Mol Neurosci 34(3):211-223

    Article  CAS  PubMed  Google Scholar 

  61. Batel P, Houchi H, Daoust M et al (2008) A haplotype of the DRD1 gene is associated with alcohol dependence. Alcohol Clin Exp Res 32(4):567-572

    Article  CAS  PubMed  Google Scholar 

  62. Hettinger JA, Liu X, Schwartz CE et al (2008) A DRD1 haplotype is associated with risk for autism spectrum disorders in male-only affected sib-pair families. Am J Med Genet B Neuropsychiatr Genet 147B(5):628-636

    Article  CAS  PubMed  Google Scholar 

  63. Lane HY, Liu YC, Huang CL et al (2008) Prefrontal executive function and D1, D3, 5-HT2A and 5-HT6 receptor gene variations in healthy adults. J Psychiatry Neurosci 33(1):47-53

    PubMed  Google Scholar 

  64. Rouillon C, Abraini JH, David HN (2008) Prefrontal cortex and basolateral amygdala modulation of dopamine-mediated locomotion in the nucleus accumbens core. Exp Neurol 212(1):213-217

    Article  CAS  PubMed  Google Scholar 

  65. Diaz Heijtz R, Castellanos FX (2006) Differential effects of a selective dopamine D1-like receptor agonist on motor activity and c-fos expression in the frontal-striatal circuitry of SHR and Wistar-Kyoto rats. Behav Brain Funct 26:2-18

    Google Scholar 

  66. Doherty JM, Masten VL, Powell SB et al (2008) Contributions of dopamine D1, D2 and D3 receptor subtypes to the disruptive effects of cocaine on prepulse inhibition in mice. Neuropsychopharmacol 33(11):2648-2656

    Article  CAS  Google Scholar 

  67. Granado N, Ortiz O, Suárez LM et al (2008) D1 but not D5 dopamine receptors are critical for LTP, spatial learning, and LTP-Induced arc and zif268 expression in the hippocampus. Cereb Cortex 18(1):1-12

    Article  PubMed  Google Scholar 

  68. Okubo Y, Suhara T, Suzuki K et al (1997) Decreased prefrontal dopamine D1 receptor in schizophrenia revealed by PET. Nature 385:578-579

    Article  Google Scholar 

  69. Tracy JI, de Leon J, Qureshi G et al (1996) Repetitive behaviors in schizophrenia: a single disturbance or discrete symptoms? Schizophr Res 20(1-2):221-229

    Article  CAS  PubMed  Google Scholar 

  70. Berridge KC, Aldridge JW (2000) Super-stereotypx. I. Enhancement of a complex movement sequence by systemic dopamine D1agonists. Synapse 37(3):194-204

    Article  CAS  PubMed  Google Scholar 

  71. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85(14):5274-5278

    Article  PubMed  Google Scholar 

  72. Froehlich JC, Harts J, Lumeng L et al (1988) Differences in response to the aversive properties of ethanol in rats selectively bred for oral ethanol preference. Pharmacol Biochem Behav 31(1):215-222

    Article  CAS  PubMed  Google Scholar 

  73. Fumagalli F, Pasquale L, Racagni G et al (2006) Dynamic regulation of fibroblast growth factor 2 (FGF-2) gene expression in the rat brain following single and repeated cocaine administration. J Neurochem 96(4):996-1004

    Article  CAS  PubMed  Google Scholar 

  74. Fumagalli F, Franchi C, Caffino L et al (2008) Single session of cocaine intravenous self-administration shapes goal-oriented behaviours and up-regulates Arc mRNA levels in rat medial prefrontal cortex. Int J Neuropsycho-pharmacol 25:1-7

    Google Scholar 

  75. Li A, Guo H, Luo X et al (2006) Apomorphine-induced activation of dopamine receptors modulates FGF-2 expression in astrocytic cultures and promotes survival of dopaminergic neurons. FASEB J 20(8):1263-1265

    Article  CAS  PubMed  Google Scholar 

  76. Roceri M, Molteni R, Fumagalli F et al (2001) Stimulatroy role of dopamine on fibroblast growth factor-2 expression in rat striatum. J Neurochem 76(4):990-997

    Article  CAS  PubMed  Google Scholar 

  77. Moro H, Sato H, Ida I et al (2007) Effects of SKF-38393, a dopamine D1 receptor agonist on expression of amphetamine-induced behavioral sensitization and expression of immediate early gene arc in prefrontal cortex of rats. Pharmacol Biochem Behav 87(1):56-64

    Article  CAS  PubMed  Google Scholar 

  78. Caine SB, Thomsen M, Gabriel KI et al (2007) Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice. J Neurosci 27(48):13140-13150

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Neurobiology, Department Animal Models, Radboud University of Nijmegen, Nijmegen, The Netherlands

    Mareike Müller, Jocelien Olivier & Judith Homberg

Authors
  1. Mareike Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jocelien Olivier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Judith Homberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Judith Homberg .

Editor information

Editors and Affiliations

  1. School of Medicine, Tulane University, Tulane Ave. 1430, New Orleans, 70112, U.S.A.

    Allan V. Kalueff

  2. E. Pittsburgh Ave. 235, Milwaukee, 53204, U.S.A.

    Carisa L. Bergner

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press, a part of Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Müller, M., Olivier, J., Homberg, J. (2010). Knockout and Mutant Rats. In: Kalueff, A., Bergner, C. (eds) Transgenic and Mutant Tools to Model Brain Disorders. Neuromethods, vol 44. Humana Press. https://doi.org/10.1007/978-1-60761-474-6_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-474-6_2

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-473-9

  • Online ISBN: 978-1-60761-474-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation