Neurophysiological Assessment of Huntington’s Disease Model Mice

  • Elissa J. Donzis
  • Sandra M. Holley
  • Carlos Cepeda
  • Michael S. LevineEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1780)


Electrophysiological and cell imaging techniques are powerful tools for understanding alterations in neuronal activity in Huntington’s disease (HD), a fatal neurological disorder caused by an expansion of CAG repeats in the HTT gene. Changes in neuronal activity often precede the behavioral manifestations of HD, therefore, understanding the electrophysiology of HD is critical for identifying potential prodromal markers and therapeutic targets. This chapter outlines the basic methodology behind four major electrophysiological and imaging techniques used in HD mouse models: patch clamp recordings, optogenetics, in vivo electrophysiology, and Ca2+ imaging, as well as some of the advancements in HD research using each of these techniques.

Key words

Electrophysiology Patch clamp Slice recordings Optogenetics Calcium imaging In vivo recordings 



The authors would like to acknowledge support from NIH grants NS96994, NS41574, and the CHDI.


  1. 1.
    Haddad MS, Cummings JL (1997) Huntington’s disease. Psychiatr Clin North Am 20:791–807CrossRefPubMedGoogle Scholar
  2. 2.
    Levine MS, Cepeda C, Hickey MA et al (2004) Genetic mouse models of Huntington’s and Parkinson’s diseases: illuminating but imperfect. Trends Neurosci 27:691–697CrossRefPubMedGoogle Scholar
  3. 3.
    Cepeda C, Starling AJ, Wu N et al (2004) Increased GABAergic function in mouse models of Huntington’s disease: reversal by BDNF. J Neurosci Res 78:855–867CrossRefPubMedGoogle Scholar
  4. 4.
    Dvorzhak A, Semtner M, Faber DS, Grantyn R (2013) Tonic mGluR5/CB1-dependent suppression of inhibition as a pathophysiological hallmark in the striatum of mice carrying a mutant form of huntingtin. J Physiol 591:1145–1166CrossRefPubMedGoogle Scholar
  5. 5.
    Cepeda C, Hurst RS, Calvert CR et al (2003) Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease. J Neurosci 23:961–969CrossRefPubMedGoogle Scholar
  6. 6.
    Cummings DM, Cepeda C, Levine MS (2010) Alterations in striatal synaptic transmission are consistent across genetic mouse models of Huntington’s disease. ASN Neuro 2:e00036CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Heikkinen T, Lehtimaki K, Vartiainen N et al (2012) Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington’s disease. PLoS One 7:e50717CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Indersmitten T, Tran CH, Cepeda C, Levine MS (2015) Altered excitatory and inhibitory inputs to striatal medium-sized spiny neurons and cortical pyramidal neurons in the Q175 mouse model of Huntington’s disease. J Neurophysiol 113:2953–2966CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Joshi PR, Wu NP, Andre VM, Cummings DM et al (2009) Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease. J Neurosci 29:2414–2427CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kolodziejczyk K, Raymond LA (2016) Differential changes in thalamic and cortical excitatory synapses onto striatal spiny projection neurons in a Huntington disease mouse model. Neurobiol Dis 86:62–74CrossRefPubMedGoogle Scholar
  11. 11.
    Cummings DM, Andre VM, Uzgil BO et al (2009) Alterations in cortical excitation and inhibition in genetic mouse models of Huntington’s disease. J Neurosci 29:10371–10386CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Milnerwood AJ, Raymond LA (2007) Corticostriatal synaptic function in mouse models of Huntington’s disease: early effects of huntingtin repeat length and protein load. J Physiol 585:817–831CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Holley SM, Joshi PR, Parievsky A et al (2015) Enhanced GABAergic inputs contribute to functional alterations of cholinergic interneurons in the R6/2 mouse model of Huntington’s disease. eNeuro 2(1):0008–0014CrossRefGoogle Scholar
  14. 14.
    Tanimura A, Lim SA, Aceves Buendia JJ et al (2016) Cholinergic interneurons amplify corticostriatal synaptic responses in the Q175 model of Huntington’s disease. Front Syst Neurosci 10:102CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cepeda C, Galvan L, Holley SM et al (2013) Multiple sources of striatal inhibition are differentially affected in Huntington’s disease mouse models. J Neurosci 33:7393–7406CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Miller BR, Walker AG, Barton SJ, Rebec GV (2011) Dysregulated neuronal activity patterns implicate corticostriatal circuit dysfunction in multiple rodent models of Huntington’s disease. Front Syst Neurosci 5:26CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Miller BR, Walker AG, Shah AS et al (2008) Dysregulated information processing by medium spiny neurons in striatum of freely behaving mouse models of Huntington’s disease. J Neurophysiol 100:2205–2216CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hong SL, Cossyleon D, Hussain WA et al (2012) Dysfunctional behavioral modulation of corticostriatal communication in the R6/2 mouse model of Huntington’s disease. PLoS One 7:e47026CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Callahan JW, Abercrombie ED (2015) Relationship between subthalamic nucleus neuronal activity and electrocorticogram is altered in the R6/2 mouse model of Huntington’s disease. J Physiol 593:3727–3738CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Walker AG, Miller BR, Fritsch JN et al (2008) Altered information processing in the prefrontal cortex of Huntington’s disease mouse models. J Neurosci 28:8973–8982CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Callahan JW, Abercrombie ED (2015) Age-dependent alterations in the cortical entrainment of subthalamic nucleus neurons in the YAC128 mouse model of Huntington’s disease. Neurobiol Dis 78:88–99CrossRefPubMedGoogle Scholar
  22. 22.
    Fisher SP, Black SW, Schwartz MD et al (2013) Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington’s disease. Brain 136:2159–2172CrossRefPubMedGoogle Scholar
  23. 23.
    Peron S, Chen TW, Svoboda K (2015) Comprehensive imaging of cortical networks. Curr Opin Neurobiol 32:115–123CrossRefPubMedGoogle Scholar
  24. 24.
    Estrada-Sanchez AM, Donzis E, Indersmitten et al (2016) Impaired functional dynamics of motor cortex microcircuits in mouse models of Huntington’s disease. Society for Neuroscience. Program No. 226.215Google Scholar
  25. 25.
    Hamill OP, Marty A, Neher E et al (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391:85–100CrossRefPubMedGoogle Scholar
  26. 26.
    Towne C, Thompson KR (2016) Overview on research and clinical applications of optogenetics. Curr Protoc Pharmacol 75:11.19.11–11.19.21Google Scholar
  27. 27.
    Deisseroth K (2015) Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci 18:1213–1225CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Connor JA, Petrozzino J, Pozzo-Miller LD, Otani S (1999) Calcium signals in long-term potentiation and long-term depression. Can J Physiol Pharmacol 77:722–734CrossRefPubMedGoogle Scholar
  29. 29.
    Garaschuk O, Milos RI, Konnerth A (2006) Targeted bulk-loading of fluorescent indicators for two-photon brain imaging in vivo. Nat Protoc 1:380–386CrossRefPubMedGoogle Scholar
  30. 30.
    Stosiek C, Garaschuk O, Holthoff K, Konnerth A (2003) In vivo two-photon calcium imaging of neuronal networks. Proc Natl Acad Sci U S A 100:7319–7324CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Soudais C, Skander N, Kremer EJ (2004) Long-term in vivo transduction of neurons throughout the rat CNS using novel helper-dependent CAV-2 vectors. FASEB J 18:391–393CrossRefPubMedGoogle Scholar
  32. 32.
    Dittgen T, Nimmerjahn A, Komai S et al (2004) Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo. Proc Natl Acad Sci U S A 101:18206–18211CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lilley CE, Branston RH, Coffin RS (2001) Herpes simplex virus vectors for the nervous system. Curr Gene Ther 1:339–358CrossRefPubMedGoogle Scholar
  34. 34.
    Ting JT, Daigle TL, Chen Q, Feng G (2014) Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. Methods Mol Biol 1183:221–242CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Akaike N (1996) Gramicidin perforated patch recording and intracellular chloride activity in excitable cells. Prog Biophys Mol Biol 65:251–264CrossRefPubMedGoogle Scholar
  36. 36.
    Gunaydin LA, Yizhar O, Berndt A et al (2010) Ultrafast optogenetic control. Nat Neurosci 13:387–392CrossRefPubMedGoogle Scholar
  37. 37.
    Klapoetke NC, Murata Y, Kim SS et al (2014) Independent optical excitation of distinct neural populations. Nat Methods 11:338–346CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Buzsaki G, Stark E, Berenyi A et al (2015) Tools for probing local circuits: high-density silicon probes combined with optogenetics. Neuron 86:92–105CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Shobe JL, Claar LD, Parhami S et al (2015) Brain activity mapping at multiple scales with silicon microprobes containing 1,024 electrodes. J Neurophysiol 114:2043–2052CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Polikov VS, Tresco PA, Reichert WM (2005) Response of brain tissue to chronically implanted neural electrodes. J Neurosci Methods 148:1–18CrossRefPubMedGoogle Scholar
  41. 41.
    Shih AY, Mateo C, Drew PJ et al (2012) A polished and reinforced thinned-skull window for long-term imaging of the mouse brain. J Vis Exp (61).
  42. 42.
    Cai DJ, Aharoni D, Shuman T et al (2016) A shared neural ensemble links distinct contextual memories encoded close in time. Nature 534:115–118CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Flusberg BA, Nimmerjahn A, Cocker ED et al (2008) High-speed, miniaturized fluorescence microscopy in freely moving mice. Nat Methods 5:935–938CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Elissa J. Donzis
    • 1
  • Sandra M. Holley
    • 1
  • Carlos Cepeda
    • 1
  • Michael S. Levine
    • 1
    Email author
  1. 1.Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human BehaviorUniversity of California Los AngelesLos AngelesUSA

Personalised recommendations