Skip to main content
SpringerLink
Log in

Generating Excitotoxic Lesion Models of Huntington’s Disease

  • Protocol
  • First Online:
Book cover Huntington’s Disease

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1780))

Abstract

In Huntington’s disease (HD), the medium spiny projection neurons of the neostriatum degenerate early in the course of the disease. While genetic mutant models of HD provide an excellent resource for studying the molecular and cellular effects of the inherited polyQ huntingtin mutation, they do not typically present with overt atrophy of the basal ganglia, despite this being a major pathophysiological hallmark of the disease. By contrast, excitotoxic lesion models, which use quinolinic acid to specifically target the striatal projection neurons, are employed to study the functional consequences of striatal atrophy and to investigate potential therapeutic interventions that target the neuronal degeneration. This chapter provides a detailed guide to the generation of excitotoxic lesion models of HD in rats.

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 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
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

References

  1. Dunnett S, Brooks S (2018) Motor assessment in Huntington’s disease mice. In: Precious S, Rosser A, Dunnett S (eds) Methods in molecular biology. Huntington’s disease. Springer protocols. Humana Press, New York

    Google Scholar 

  2. Fareham P, Bates G (2018) Mouse models of Huntington’s disease. In: Precious S, Rosser A, Dunnett S (eds) Methods in molecular biology. Huntington’s disease. Springer protocols. Humana Press, New York

    Google Scholar 

  3. Vonsattel JP, Myers RH, Stevens TJ et al (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577

    Article  CAS  PubMed  Google Scholar 

  4. Tabrizi SJ, Scahill RI, Owen G et al (2013) Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol 12:637–649

    Article  PubMed  Google Scholar 

  5. Braak H, Braak E (1992) Allocortical involvement in Huntington’s disease. Neuropathol Appl Neurobiol 18:539–547

    Article  CAS  PubMed  Google Scholar 

  6. Hedreen JC, Peyser CE, Folstein SE, Ross CA (1991) Neuronal loss in layers V and VI of cerebral cortex in Huntington’s disease. Neurosci Lett 133:257–261

    Article  CAS  PubMed  Google Scholar 

  7. Heinsen H, Strik M, Bauer M et al (1994) Cortical and striatal neurone number in Huntington’s disease. Acta Neuropathol 88:320–333

    Article  CAS  PubMed  Google Scholar 

  8. Rüb U, Hentschel M, Stratmann K et al (2014) Huntington’s disease (HD): degeneration of select nuclei, widespread occurrence of neuronal nuclear and axonal inclusions in the brainstem. Brain Pathol 24:247–260. https://doi.org/10.1111/bpa.12115

    Article  PubMed  PubMed Central  Google Scholar 

  9. Beal MF, Kowall NW, Swartz KJ et al (1989) Differential sparing of somatostatin-neuropeptide y and cholinergic neurons following striatal excitotoxin lesions. Synapse 3:38–47

    Article  CAS  PubMed  Google Scholar 

  10. el-Defrawy SR, Boegman RJ, Jhamandas K, Beninger RJ (1986) The neurotoxic actions of quinolinic acid in the central nervous system. Can J Physiol Pharmacol 64:369–375

    Article  CAS  PubMed  Google Scholar 

  11. Köhler C, Schwarcz R (1983) Comparison of ibotenate and kainate neurotoxicity in rat brain: a histological study. Neuroscience 8:819–835

    Article  PubMed  Google Scholar 

  12. Schwarcz R, Köhler C (1983) Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci Lett 38:85–90

    Article  CAS  PubMed  Google Scholar 

  13. Beal MF, Kowall NW, Ellison DW et al (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321:168–171

    Article  CAS  PubMed  Google Scholar 

  14. Beal MF, Ferrante RJ, Swartz KJ, Kowall NW (1991) Chronic quinolinic acid lesions in rats closely resemble Huntington’s disease. J Neurosci 11:1649–1659

    Article  CAS  PubMed  Google Scholar 

  15. Dawbarn D, De Quidt ME, Emson PC (1985) Survival of basal ganglia neuropeptide Y-somatostatin neurones in Huntington’s disease. Brain Res 340:251–260

    Article  CAS  PubMed  Google Scholar 

  16. Ferrante RJ, Kowall NW, Beal MF et al (1985) Selective sparing of a class of striatal neurons in Huntington’s disease. Science 230:561–563

    Article  CAS  PubMed  Google Scholar 

  17. Lelos MJ, Harrison DJ, Rosser AE, Dunnett SB (2013) The lateral neostriatum is necessary for compensatory ingestive behaviour after intravascular dehydration in female rats. Appetite 71:287–294

    Article  CAS  PubMed  Google Scholar 

  18. Brasted PJ, Humby T, Dunnett SB, Robbins TW (1997) Unilateral lesions of the dorsal striatum in rats disrupt responding in egocentric space. J Neurosci 17:8919–8926

    Article  CAS  PubMed  Google Scholar 

  19. Lelos MJ, Harrison DJ, Dunnett SB (2011) Impaired sensitivity to Pavlovian stimulus-outcome learning after excitotoxic lesion of the ventrolateral neostriatum. Behav Brain Res 225:522–528

    Article  PubMed  Google Scholar 

  20. Voorn P, Vanderschuren LJ, Groenewegen HJ et al (2004) Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci 27:468–474

    Article  CAS  PubMed  Google Scholar 

  21. Döbrössy MD, Dunnett SB (2006) The effects of lateralized training on spontaneous forelimb preference, lesion deficits, and graft-mediated functional recovery after unilateral striatal lesions in rats. Exp Neurol 199:373–383

    Article  PubMed  Google Scholar 

  22. Dobrossy MD, Dunnett SB (2005) Training specificity, graft development and graft-mediated functional recovery in a rodent model of Huntington’s disease. Neuroscience 132:543–552

    Article  CAS  PubMed  Google Scholar 

  23. Klein A, Lane EL, Dunnett SB (2013) Brain repair in a unilateral rat model of Huntington’s disease: new insights into impairment and restoration of forelimb movement patterns. Cell Transplant 22:1735–1751

    Article  PubMed  Google Scholar 

  24. Lelos MJ, Roberton VH, Vinh N-N et al (2016) Direct comparison of rat- and human-derived ganglionic eminence tissue grafts on motor function. Cell Transplant 25:665–675

    Article  PubMed  Google Scholar 

  25. Tartaglione AM, Armida M, Potenza RL et al (2016) Aberrant self-grooming as early marker of motor dysfunction in a rat model of Huntington’s disease. Behav Brain Res 313:53–57

    Article  CAS  PubMed  Google Scholar 

  26. Scattoni ML, Valanzano A, Popoli P et al (2004) Progressive behavioural changes in the spatial open-field in the quinolinic acid rat model of Huntington’s disease. Behav Brain Res 152:375–383

    Article  PubMed  Google Scholar 

  27. Trueman RC, Brooks SP, Dunnett SB (2005) Implicit learning in a serial choice visual discrimination task in the operant 9-hole box by intact and striatal lesioned mice. Behav Brain Res 159:313–322

    Article  PubMed  Google Scholar 

  28. Yin HH, Knowlton BJ, Balleine BW (2004) Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning. Eur J Neurosci 19:181–189

    Article  PubMed  Google Scholar 

  29. Featherstone RE, McDonald RJ (2005) Lesions of the dorsolateral striatum impair the acquisition of a simplified stimulus-response dependent conditional discrimination task. Neuroscience 136:387–395

    Article  CAS  PubMed  Google Scholar 

  30. Lindgren HS, Wickens R, Tait DS et al (2013) Lesions of the dorsomedial striatum impair formation of attentional set in rats. Neuropharmacology 71:148–153

    Article  CAS  PubMed  Google Scholar 

  31. Castañé A, Theobald DEH, Robbins TW (2010) Selective lesions of the dorsomedial striatum impair serial spatial reversal learning in rats. Behav Brain Res 210:74–83

    Article  PubMed  PubMed Central  Google Scholar 

  32. Dunnett SB, White A (2006) Striatal grafts alleviate bilateral striatal lesion deficits in operant delayed alternation in the rat. Exp Neurol 199:479–489

    Article  PubMed  Google Scholar 

  33. Eagle DM, Humby T, Dunnett SB, Robbins TW (1999) Effects of regional striatal lesions on motor, motivational, and executive aspects of progressive-ratio performance in rats. Behav Neurosci 113:718–731

    Article  CAS  PubMed  Google Scholar 

  34. Kendall AL, David F, Rayment G et al (2000) The influence of excitotoxic basal ganglia lesions on motor performance in the common marmoset. Brain 123:1442–1458

    Article  PubMed  Google Scholar 

  35. Skaggs K, Goldman D, Parent JM (2014) Excitotoxic brain injury in adult zebrafish stimulates neurogenesis and long-distance neuronal integration. Glia 62:2061–2079

    Article  PubMed  PubMed Central  Google Scholar 

  36. Brooks SP, Trueman RC, Dunnett SB (2007) Striatal lesions in the mouse disrupt acquisition and retention, but not implicit learning, in the SILT procedural motor learning task. Brain Res 1185:179–188

    Article  CAS  PubMed  Google Scholar 

  37. Lelos MJ, Harrison DJ, Dunnett SB (2012) Intrastriatal excitotoxic lesion or dopamine depletion of the neostriatum differentially impairs response execution in extrapersonal space. Eur J Neurosci 36:3420–3428

    Article  CAS  PubMed  Google Scholar 

  38. Dunnett SB, Heuer A, Lelos M et al (2012) Bilateral striatal lesions disrupt performance in an operant delayed reinforcement task in rats. Brain Res Bull 88:251–260

    Article  PubMed  Google Scholar 

  39. Brasted PJ, Dobrossy MD, Robbins TW, Dunnett SB (1998) Striatal lesions produce distinctive impairments in reaction time performance in two different operant chambers. Brain Res Bull 46:487–493

    Article  CAS  PubMed  Google Scholar 

  40. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, London

    Google Scholar 

  41. Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, London

    Google Scholar 

  42. Burns LH, Pakzaban P, Deacon TW et al (1995) Selective putaminal excitotoxic lesions in non-human primates model the movement disorder of Huntington disease. Neuroscience 64:1007–1017

    Article  CAS  PubMed  Google Scholar 

  43. Brownell AL, Hantraye P, Wullner U et al (1994) PET- and MRI-based assessment of glucose utilization, dopamine receptor binding, and hemodynamic changes after lesions to the caudate-putamen in primates. Exp Neurol 125:41–51

    Article  CAS  PubMed  Google Scholar 

  44. Sugimoto T, Mizuno N (1987) Quinolinic and kainic acids can enhance calcitonin gene-related peptide-like immunoreactivity in striatal neurons with substance P-like immunoreactivity. Brain Res 418:392–397

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Our own work in this area has been supported by funding from the Medical Research Council, the EU FP7 Repair HD and NeuroStemCell Repair consortia, and Parkinson’s UK charity. We thank David Harrison for generating photographic material for the figure.

Author information

Authors and Affiliations

  1. Brain Repair Group, School of Biosciences, Cardiff University, Wales, UK

    Mariah J. Lelos

  2. Brain Repair Group, Cardiff University, Cardiff, UK

    Stephen B. Dunnett

Authors
  1. Mariah J. Lelos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen B. Dunnett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mariah J. Lelos .

Editor information

Editors and Affiliations

  1. Brain Repair Group, Cardiff University, Cardiff, United Kingdom

    Sophie V. Precious

  2. Brain Repair Group, Cardiff University, Cardiff, United Kingdom

    Anne E. Rosser

  3. Brain Repair Group, Cardiff University, Cardiff, United Kingdom

    Stephen B. Dunnett

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Lelos, M.J., Dunnett, S.B. (2018). Generating Excitotoxic Lesion Models of Huntington’s Disease. In: Precious, S., Rosser, A., Dunnett, S. (eds) Huntington’s Disease. Methods in Molecular Biology, vol 1780. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7825-0_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-7825-0_11

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7824-3

  • Online ISBN: 978-1-4939-7825-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation