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Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism

Molecular Psychiatry volume 22, pages 595–604 (2017)Cite this article

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Abstract

Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2−/− mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson’s disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette’s syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.

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References

  1. Yin HH, Knowlton BJ . The role of the basal ganglia in habit formation. Nat Rev Neurosci 2006; 7: 464–476.

    Article  CAS  Google Scholar 

  2. Graybiel AM, Aosaki T, Flaherty AW, Kimura M . The basal ganglia and adaptive motor control. Science 1994; 265: 1826–1831.

    Article  CAS  Google Scholar 

  3. Gerfen CR, Surmeier DJ . Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 2011; 34: 441–466.

    Article  CAS  Google Scholar 

  4. Kravitz AV, Freeze BS, Parker PRL, Kay K, Thwin MT, Deisseroth K et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 2010; 466: 622–626.

    Article  CAS  Google Scholar 

  5. Ralph RJ, Caine SB . Dopamine D1 and D2 agonist effects on prepulse inhibition and locomotion: comparison of Sprague-Dawley rats to Swiss-Webster, 129X1/SvJ, C57BL/6J, and DBA/2J mice. J Pharmacol Exp Ther 2005; 312: 733–741.

    Article  CAS  Google Scholar 

  6. Thomsen M, Ralph RJ, Caine SB . Psychomotor stimulation by dopamine D1-like but not D2-like agonists in most mouse strains. Exp Clin Psychopharmacol 2011; 19: 342–360.

    Article  CAS  Google Scholar 

  7. Maurice N . D2 dopamine receptor-mediated modulation of voltage-dependent Na+ Channels reduces autonomous activity in striatal cholinergic interneurons. J Neurosci 2004; 24: 10289–10301.

    Article  CAS  Google Scholar 

  8. Wang Z, Kai L, Day M, Ronesi J, Yin HH, Ding J et al. Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons. Neuron 2006; 50: 443–452.

    Article  CAS  Google Scholar 

  9. Bamford NS, Zhang H, Schmitz Y, Wu N-P, Cepeda C, Levine MS et al. Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals. Neuron 2004; 42: 653–663.

    Article  CAS  Google Scholar 

  10. Bello EP, Mateo Y, Gelman DM, Noaín D, Shin JH, Low MJ et al. Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci 2011; 14: 1033–1038.

    Article  CAS  Google Scholar 

  11. Ford CP . The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience 2014; 282C: 13–22.

    Article  Google Scholar 

  12. Noaín D, Pérez-Millán MI, Bello EP, Luque GM, Casas Cordero R, Gelman DM et al. Central dopamine D2 receptors regulate growth-hormone-dependent body growth and pheromone signaling to conspecific males. J Neurosci 2013; 33: 5834–5842.

    Article  Google Scholar 

  13. Holroyd KB, Adrover MF, Fuino RL, Bock R, Kaplan AR, Gremel CM et al. Loss of feedback inhibition via D2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues. Neuropsychopharmacology 2015; 40: 1495–1509.

    Article  CAS  Google Scholar 

  14. Perez Millan MI, Luque GM, Ramirez MC, Noain D, Ornstein AM, Rubinstein M et al. Selective disruption of dopamine D2 receptors in pituitary lactotropes increases body weight and adiposity in female mice. Endocrinology 2014; 155: 829–839.

    Article  Google Scholar 

  15. Anzalone A, Lizardi-Ortiz JE, Ramos M, De Mei C, Hopf FW, Iaccarino C et al. Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J Neurosci 2012; 32: 9023–9034.

    Article  CAS  Google Scholar 

  16. Fujiwara H . Comparative studies of sulpiride and classical neuroleptics on induction of catalepsy, locomotor activity, and brain dopamine metabolism in mice. Pharmacol Biochem Behav 1992; 41: 301–308.

    Article  CAS  Google Scholar 

  17. Caroff SN, Hurford I, Lybrand J, Campbell EC . Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin 2011; 29: 127–148, viii.

    Article  Google Scholar 

  18. Zhou QY, Palmiter RD . Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 1995; 83: 1197–1209.

    Article  CAS  Google Scholar 

  19. Kelly MA, Rubinstein M, Phillips TJ, Lessov CN, Burkhart-Kasch S, Zhang G et al. Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J Neurosci 1998; 18: 3470–3479.

    Article  CAS  Google Scholar 

  20. Clifford JJ, Usiello A, Vallone D, Kinsella A, Borrelli E, Waddington JL . Topographical evaluation of behavioural phenotype in a line of mice with targeted gene deletion of the D2 dopamine receptor. Neuropharmacology 2000; 39: 382–390.

    Article  CAS  Google Scholar 

  21. Clifford JJ, Kinsella A, Tighe O, Rubinstein M, Grandy DK, Low MJ et al. Comparative, topographically-based evaluation of behavioural phenotype and specification of D(1)-like:D(2) interactions in a line of incipient congenic mice with D(2) dopamine receptor 'knockout'. Neuropsychopharmacology 2001; 25: 527–536.

    Article  CAS  Google Scholar 

  22. Hayashi S, McMahon AP . Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 2002; 244: 305–318.

    Article  CAS  Google Scholar 

  23. Pascual A, Hidalgo-Figueroa M, Piruat JI, Pintado CO, Gómez-Díaz R, López-Barneo J . Absolute requirement of GDNF for adult catecholaminergic neuron survival. Nat Neurosci 2008; 11: 755–761.

    Article  CAS  Google Scholar 

  24. Nguyen MV, Du F, Felice CA, Shan X, Nigam A, Mandel G et al. MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. J Neurosci 2012; 32: 10021–10034.

    Article  CAS  Google Scholar 

  25. Pelosi B, Pratelli M, Migliarini S, Pacini G, Pasqualetti M . Generation of a Tph2 conditional knockout mouse line for time- and tissue-specific depletion of brain serotonin. PLoS One 2015; 10: e0136422.

    Article  Google Scholar 

  26. Bumaschny VF, Yamashita M, Casas-Cordero R, Otero-Corchón V, de Souza FS, Rubinstein M et al. Obesity-programmed mice are rescued by early genetic intervention. J Clin Invest 2012; 122: 4203–4212.

    Article  CAS  Google Scholar 

  27. Hammond C, Bergman H, Brown P . Pathological synchronization in Parkinson’s disease: networks, models and treatments. Trends Neurosci 2007; 30: 357–364.

    Article  CAS  Google Scholar 

  28. Stein E, Bar-Gad I . Beta oscillations in the cortico-basal ganglia loop during parkinsonism. Exp Neurol 2013; 245: 52–59.

    Article  Google Scholar 

  29. Mallet N, Pogosyan A, Sharott A, Csicsvari J, Bolam JP, Brown P et al. Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex. J Neurosci 2008; 28: 4795–4806.

    Article  CAS  Google Scholar 

  30. Connolly AT, Jensen AL, Bello EM, Netoff TI, Baker KB, Johnson MD et al. Modulations in oscillatory frequency and coupling in globus pallidus with increasing parkinsonian severity. J Neurosci 2015; 35: 6231–6240.

    Article  CAS  Google Scholar 

  31. Costa RM, Lin S-C, Sotnikova TD, Cyr M, Gainetdinov RR, Caron MG et al. Rapid alterations in corticostriatal ensemble coordination during acute dopamine-dependent motor dysfunction. Neuron 2006; 52: 359–369.

    Article  CAS  Google Scholar 

  32. Walters JR, Hu D, Itoga CA, Parr-Brownlie LC, Bergstrom DA . Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine. Neuroscience 2007; 144: 762–776.

    Article  CAS  Google Scholar 

  33. Zold CL, Ballion B, Riquelme LA, Gonon F, Murer MG . Nigrostriatal lesion induces D2-modulated phase-locked activity in the basal ganglia of rats. Eur J Neurosci 2007; 25: 2131–2144.

    Article  Google Scholar 

  34. Mallet N, Pogosyan A, Márton LF, Bolam JP, Brown P, Magill PJ . Parkinsonian beta oscillations in the external globus pallidus and their relationship with subthalamic nucleus activity. J Neurosci 2008; 28: 14245–14258.

    Article  CAS  Google Scholar 

  35. Zold CL, Larramendy C, Riquelme LA, Murer MG . Distinct changes in evoked and resting globus pallidus activity in early and late Parkinson’s disease experimental models. Eur J Neurosci 2007; 26: 1267–1279.

    Article  Google Scholar 

  36. Zold CL, Escande MV, Pomata PE, Riquelme LA, Murer MG . Striatal NMDA receptors gate cortico-pallidal synchronization in a rat model of Parkinson’s disease. Neurobiol Dis 2012; 47: 38–48.

    Article  CAS  Google Scholar 

  37. Mallet N, Micklem BR, Henny P, Brown MT, Williams C, Bolam JP et al. Dichotomous organization of the external globus pallidus. Neuron 2012; 74: 1075–1086.

    Article  CAS  Google Scholar 

  38. Levy R, Hazrati LN, Herrero MT, Vila M, Hassani OK, Mouroux M et al. Re-evaluation of the functional anatomy of the basal ganglia in normal and Parkinsonian states. Neuroscience 1997; 76: 335–343.

    Article  CAS  Google Scholar 

  39. Kühn AA, Williams D, Kupsch A, Limousin P, Hariz M, Schneider G-H et al. Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance. Brain 2004; 127: 735–746.

    Article  Google Scholar 

  40. Brown P . Abnormal oscillatory synchronisation in the motor system leads to impaired movement. Curr Opin Neurobiol 2007; 17: 656–664.

    Article  CAS  Google Scholar 

  41. Devos D, Defebvre L . Chapter 22 Effect of deep brain stimulation and l-Dopa on electrocortical rhythms related to movement in Parkinson’s disease. Prog Brain Res 2006; 159: 331–349.

    Article  CAS  Google Scholar 

  42. Sharott A, Magill PJ, Harnack D, Kupsch A, Meissner W, Brown P . Dopamine depletion increases the power and coherence of beta-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat. Eur J Neurosci 2005; 21: 1413–1422.

    Article  Google Scholar 

  43. Amirnovin R, Williams ZM, Cosgrove GR, Eskandar EN . Visually guided movements suppress subthalamic oscillations in Parkinson’s disease patients. J Neurosci 2004; 24: 11302–11306.

    Article  CAS  Google Scholar 

  44. McCarthy MM, Moore-Kochlacs C, Gu X, Boyden ES, Han X, Kopell N . Striatal origin of the pathologic beta oscillations in Parkinson’s disease. Proc Natl Acad Sci USA 2011; 108: 11620–11625.

    Article  CAS  Google Scholar 

  45. Miyamoto S, Duncan GE, Marx CE, Lieberman JA . Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10: 79–104.

    Article  CAS  Google Scholar 

  46. Koeltzow TE, Xu M, Cooper DC, Hu XT, Tonegawa S, Wolf ME et al. Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice. J Neurosci 1998; 18: 2231–2238.

    Article  CAS  Google Scholar 

  47. Xu M, Koeltzow TE, Cooper DC, Tonegawa S, White FJ . Dopamine D3 receptor mutant and wild-type mice exhibit identical responses to putative D3 receptor-selective agonists and antagonists. Synapse 1999; 31: 210–215.

    Article  CAS  Google Scholar 

  48. Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G et al. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 1997; 90: 991–1001.

    Article  CAS  Google Scholar 

  49. Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR et al. Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 1997; 19: 103–113.

    Article  CAS  Google Scholar 

  50. Díaz-Torga G, Feierstein C, Libertun C, Gelman D, Kelly MA, Low MJ et al. Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in male mice. Endocrinology 2002; 143: 1270–1279.

    Article  Google Scholar 

  51. Susatia F, Fernandez HH . Drug-induced parkinsonism. Curr Treat Options Neurol 2009; 11: 162–169.

    Article  Google Scholar 

  52. Rocchetti J, Isingrini E, Dal BoG, Sagheby S, Menegaux A, Tronche F et al. Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus. Biol Psychiatry 2015; 77: 513–525.

    Article  CAS  Google Scholar 

  53. Cachope R, Mateo Y, Mathur BN, Irving J, Wang H-L, Morales M et al. Selective activation of cholinergic interneurons enhances accumbal phasic dopamine release: setting the tone for reward processing. Cell Rep 2012; 2: 33–41.

    Article  CAS  Google Scholar 

  54. Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ . Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 2012; 75: 58–64.

    Article  CAS  Google Scholar 

  55. Barone P, Davis TA, Braun AR, Chase TN . Dopaminergic mechanisms and motor function: characterization of D-1 and D-2 dopamine receptor interactions. Eur J Pharmacol 1986; 123: 109–114.

    Article  CAS  Google Scholar 

  56. Rubinstein M, Gershanik O, Stefano FJ . Different roles of D-1 and D-2 dopamine receptors involved in locomotor activity of supersensitive mice. Eur J Pharmacol 1988; 148: 419–426.

    Article  CAS  Google Scholar 

  57. Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 2014; 494: 238–242.

    Article  Google Scholar 

  58. Yin HH, Mulcare SP, Hilário MRF, Clouse E, Holloway T, Davis MI et al. Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill. Nat Neurosci 2009; 12: 333–341.

    Article  CAS  Google Scholar 

  59. Schwab RS, Chafetz ME, Walker S . Control of two simultaneous voluntary motor acts in normals and in parkinsonism. AMA Arch Neurol Psychiatry 1954; 72: 591–598.

    Article  CAS  Google Scholar 

  60. Knowlton BJ, Mangels JA, Squire LR . A neostriatal habit learning system in humans. Science 1996; 273: 1399–1402.

    Article  CAS  Google Scholar 

  61. Faure A, Haberland U, Condé F, El Massioui N . Lesion to the nigrostriatal dopamine system disrupts stimulus-response habit formation. J Neurosci 2005; 25: 2771–2780.

    Article  CAS  Google Scholar 

  62. Tseng KY, Kasanetz F, Kargieman L, Riquelme LA, Murer MG . Cortical slow oscillatory activity is reflected in the membrane potential and spike trains of striatal neurons in rats with chronic nigrostriatal lesions. J Neurosci 2001; 21: 6430–6439.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by grants from the Agencia Nacional de Promoción Científica y Tecnológica, Argentina (to MR and MGM), UBACYT (to MR), Tourette’s Syndrome Association (to MR) and doctoral fellowships from CONICET (to EPB, DN, RCC, EC, GLG, MAB).

Author contributions

EPB, MGM and MR designed the experiments. EPB, RCC, GLG, EC, MAB, VR and DN performed the experiments and analyzed the data. EPB, RCC, EC, VR and DN performed the behavioral and biochemistry assays. GLG and MAB performed electrophysiological recordings. EB and MR wrote the paper. MGM edited the manuscript. MR perceived and directed the project.

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Authors and Affiliations

  1. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas and Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina

    E P Bello, R Casas-Cordero, E Casey, V Rodríguez, D Noaín & M Rubinstein

  2. Instituto de Fisiología y Biofísica Bernardo Houssay, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina

    G L Galiñanes, M A Belluscio & M G Murer

  3. Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

    M G Murer

  4. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    M Rubinstein

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  1. E P Bello
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  2. R Casas-Cordero
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  3. G L Galiñanes
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  4. E Casey
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  5. M A Belluscio
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  7. D Noaín
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  8. M G Murer
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  9. M Rubinstein
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Correspondence to M Rubinstein.

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Bello, E., Casas-Cordero, R., Galiñanes, G. et al. Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism. Mol Psychiatry 22, 595–604 (2017). https://doi.org/10.1038/mp.2016.105

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