Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions

  • Christopher Pittenger
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 241)


While the normal functions of histamine (HA) in the central nervous system have gradually come into focus over the past 30 years, the relationship of abnormalities in neurotransmitter HA to human disease has been slower to emerge. New insight came with the 2010 description of a rare nonsense mutation in the biosynthetic enzyme histidine decarboxylase (Hdc) that was associated with Tourette syndrome (TS) and related conditions in a single family pedigree. Subsequent genetic work has provided further support for abnormalities of HA signaling in sporadic TS. As a result of this genetic work, Hdc knockout mice, which were generated more than 15 years ago, have been reexamined as a model of the pathophysiology of TS and related conditions. Parallel work in these KO mice and in human carriers of the Hdc mutation has revealed abnormalities in the basal ganglia system and its modulation by dopamine (DA) and has confirmed the etiologic, face, and predictive validity of the model. The Hdc-KO model thus serves as a unique platform to probe the pathophysiology of TS and related conditions, and to generate specific hypotheses for subsequent testing in humans. This chapter summarizes the development and validation of this model and recent and ongoing work using it to further investigate pathophysiological changes that may contribute to these disorders.


Animal model Histamine Histidine decarboxylase Obsessive–compulsive disorder Tic disorders Tourette syndrome 



An H3 receptor PET tracer


A PET tracer that binds to the peripheral benzodiazepine receptor, PBR, a marker of activated microglia


A PET tracer that binds to activated microglia


Attention deficit-hyperactivity disorder


Ak-thymoma protein kinase, also known as protein kinase B


Autism spectrum disorder


An H3R antagonist


C57 Black-6 inbred mouse line


Cyclic adenosine monophosphate


Copy number variation


Dopamine D1 receptor


Dopamine D2 receptor




Dopamine- and cAMP-regulated phosphoprotein


Direct/striatonigral pathway medium spiny neuron


Gamma-aminobutyric acid


Globus pallidus, pars externa


Globus pallidus, pars interna


Glycogen synthase kinase 3-beta


Genome-wide association study


Histamine H1 receptor


Histamine H2 receptor


Histamine H3 receptor


Histamine H4 receptor




Histidine decarboxylase gene


Histidine decarboxylase knockout mouse


Insulin-like growth factor 1


Interleukin 1


Indirect/striatopallidal pathway medium spiny neuron


An H3R receptor antagonist




Mitogen-activated protein kinase


Messenger ribonucleic acid


Medium spiny neuron


Obsessive–compulsive disorder


Pediatric autoimmune neuropsychiatric disorder associated with Streptococcus


Positron emission tomography




Prepulse inhibition


R-aminomethylhistamine, an H4R agonist


Supplementary motor area


Substantia nigra, pars compacta


Substantia nigra, pars reticulata


Subthalamic nucleus


Type-1 T-helper cell


Tourette syndrome


  1. Abelson JF, Kwan KY, O’Roak BJ, Baek DY, Stillman AA, Morgan TM, Mathews CA, Pauls DL, Rasin MR, Gunel M et al (2005) Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science 310:317–320PubMedCrossRefGoogle Scholar
  2. Acevedo SF, Ohtsu H, Benice TS, Rizk-Jackson A, Raber J (2006a) Age-dependent measures of anxiety and cognition in male histidine decarboxylase knockout (Hdc-/-) mice. Brain Res 1071:113–123PubMedCrossRefGoogle Scholar
  3. Acevedo SF, Pfankuch T, Ohtsu H, Raber J (2006b) Anxiety and cognition in female histidine decarboxylase knockout (Hdc(-/-)) mice. Behav Brain Res 168:92–99PubMedCrossRefGoogle Scholar
  4. Ahmari SE, Risbrough VB, Geyer MA, Simpson HB (2012) Impaired sensorimotor gating in unmedicated adults with obsessive-compulsive disorder. Neuropsychopharmacology 37:1216–1223PubMedPubMedCentralCrossRefGoogle Scholar
  5. Ahmari SE, Spellman T, Douglass NL, Kheirbek MA, Simpson HB, Deisseroth K, Gordon JA, Hen R (2013) Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science 340:1234–1239PubMedPubMedCentralCrossRefGoogle Scholar
  6. Albin RL, Mink JW (2006) Recent advances in Tourette syndrome research. Trends Neurosci 29:175–182PubMedCrossRefGoogle Scholar
  7. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375PubMedCrossRefGoogle Scholar
  8. Alfaro-Rodriguez A, Alonso-Spilsbury M, Arch-Tirado E, Gonzalez-Pina R, Arias-Montano JA, Bueno-Nava A (2013) Histamine H3 receptor activation prevents dopamine D1 receptor-mediated inhibition of dopamine release in the rat striatum: a microdialysis study. Neurosci Lett 552:5–9PubMedCrossRefGoogle Scholar
  9. Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG (2005) An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122:261–273PubMedCrossRefGoogle Scholar
  10. Bloch MH (2008) Emerging treatments for Tourette’s disorder. Curr Psychiatry Rep 10:323–330PubMedCrossRefGoogle Scholar
  11. Bloch M, State M, Pittenger C (2011) Recent advances in Tourette syndrome. Curr Opin Neurol 24:119–125PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bolam JP, Ellender TJ (2015) Histamine and the striatum. Neuropharmacology 106:74–84PubMedCrossRefGoogle Scholar
  13. Bronfeld M, Bar-Gad I (2013) Tic disorders: what happens in the basal ganglia? Neuroscientist 19:101–108PubMedCrossRefGoogle Scholar
  14. Bronfeld M, Yael D, Belelovsky K, Bar-Gad I (2013) Motor tics evoked by striatal disinhibition in the rat. Front Syst Neurosci 7:50PubMedPubMedCentralCrossRefGoogle Scholar
  15. Buse J, Kirschbaum C, Leckman JF, Munchau A, Roessner V (2014) The modulating role of stress in the onset and course of Tourette’s syndrome: a review. Behav Modif 38:184–216PubMedCrossRefGoogle Scholar
  16. Campbell KM, de Lecea L, Severynse DM, Caron MG, McGrath MJ, Sparber SB, Sun LY, Burton FH (1999) OCD-Like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+ neurons. J Neurosci 19:5044–5053PubMedGoogle Scholar
  17. Canales JJ, Graybiel AM (2000) A measure of striatal function predicts motor stereotypy. Nat Neurosci 3:377–383PubMedCrossRefGoogle Scholar
  18. Canitano R, Vivanti G (2007) Tics and Tourette syndrome in autism spectrum disorders. Autism 11:19–28PubMedCrossRefGoogle Scholar
  19. Castellan Baldan L, Williams KA, Gallezot JD, Pogorelov V, Rapanelli M, Crowley M, Anderson GM, Loring E, Gorczyca R, Billingslea E et al (2014) Histidine decarboxylase deficiency causes Tourette syndrome: parallel findings in humans and mice. Neuron 82:1186–1187CrossRefGoogle Scholar
  20. Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL, Hallett M (1996) Sensorimotor gating in boys with Tourette’s syndrome and ADHD: preliminary results. Biol Psychiatry 39:33–41PubMedCrossRefGoogle Scholar
  21. Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141:775–785PubMedPubMedCentralCrossRefGoogle Scholar
  22. Chepkova A, Yanovsky E, Parmentier R, Ohtsu H, Haas HL, Lin JS, Sergeeva OA (2012) Histamine receptor expression, hippocampal plasticity and ammonia in histidine decarboxylase knockout mice. Cell Mol Neurobiol 32:17–25PubMedCrossRefGoogle Scholar
  23. Conelea CA, Woods DW (2008) The influence of contextual factors on tic expression in Tourette’s syndrome: a review. J Psychosom Res 65:487–496PubMedCrossRefGoogle Scholar
  24. Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM, Costa RM (2013) Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494:238–242PubMedPubMedCentralCrossRefGoogle Scholar
  25. Davis LK, Yu D, Keenan CL, Gamazon ER, Konkashbaev AI, Derks EM, Neale BM, Yang J, Lee SH, Evans P et al (2013) Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet 9:e1003864PubMedPubMedCentralCrossRefGoogle Scholar
  26. Denys D, de Vries F, Cath D, Figee M, Vulink N, Veltman DJ, van der Doef TF, Boellaard R, Westenberg H, van Balkom A et al (2013) Dopaminergic activity in Tourette syndrome and obsessive-compulsive disorder. Eur Neuropsychopharmacol 23:1423–1431PubMedCrossRefGoogle Scholar
  27. Dere E, De Souza-Silva MA, Topic B, Spieler RE, Haas HL, Huston JP (2003) Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover. Learn Mem 10:510–519PubMedPubMedCentralCrossRefGoogle Scholar
  28. Dere E, De Souza-Silva MA, Spieler RE, Lin JS, Ohtsu H, Haas HL, Huston JP (2004) Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neurosci 20:1051–1058PubMedCrossRefGoogle Scholar
  29. Dringenberg HC, de Souza-Silva MA, Schwarting RK, Huston JP (1998) Increased levels of extracellular dopamine in neostriatum and nucleus accumbens after histamine H1 receptor blockade. Naunyn Schmiedebergs Arch Pharmacol 358:423–429PubMedCrossRefGoogle Scholar
  30. Du JC, Chiu TF, Lee KM, Wu HL, Yang YC, Hsu SY, Sun CS, Hwang B, Leckman JF (2010) Tourette syndrome in children: an updated review. Pediatr Neonatol 51:255–264PubMedCrossRefGoogle Scholar
  31. Elamin I, Edwards MJ, Martino D (2013) Immune dysfunction in Tourette syndrome. Behav Neurol 27:23–32PubMedPubMedCentralCrossRefGoogle Scholar
  32. Ellender TJ, Huerta-Ocampo I, Deisseroth K, Capogna M, Bolam JP (2011) Differential modulation of excitatory and inhibitory striatal synaptic transmission by histamine. J Neurosci 31:15340–15351PubMedCrossRefGoogle Scholar
  33. Ercan-Sencicek AG, Stillman AA, Ghosh AK, Bilguvar K, O’Roak BJ, Mason CE, Abbott T, Gupta A, King RA, Pauls DL et al (2010) L-histidine decarboxylase and Tourette’s syndrome. N Engl J Med 362:1901–1908PubMedPubMedCentralCrossRefGoogle Scholar
  34. Falus A, Grosman N, Darvas Z (2004) Histamine: biology and medical aspects. Karger; SpringMed Pub, Basel; Budapest, pp 43–52Google Scholar
  35. Fauchey V, Jaber M, Caron MG, Bloch B, Le Moine C (2000) Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter. Eur J Neurosci 12:19–26PubMedCrossRefGoogle Scholar
  36. Feinberg M, Carroll BJ (1979) Effects of dopamine agonists and antagonists in Tourette’s disease. Arch Gen Psychiatry 36:979–985PubMedCrossRefGoogle Scholar
  37. Fernandez TV, Sanders SJ, Yurkiewicz IR, Ercan-Sencicek AG, Kim YS, Fishman DO, Raubeson MJ, Song Y, Yasuno K, Ho WS et al (2012) Rare copy number variants in Tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry 71:392–402PubMedCrossRefGoogle Scholar
  38. Fernandez T, State MW, Pittenger C (2017) Tourette’s disorder and tic disorders. In: Geschwind DH, Paulson HL (eds) Neurogenetics. Elsevier, New York, NYGoogle Scholar
  39. Ferrada C, Ferre S, Casado V, Cortes A, Justinova Z, Barnes C, Canela EI, Goldberg SR, Leurs R, Lluis C et al (2008) Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function. Neuropharmacology 55:190–197PubMedCrossRefGoogle Scholar
  40. Ferrada C, Moreno E, Casado V, Bongers G, Cortes A, Mallol J, Canela EI, Leurs R, Ferre S, Lluis C et al (2009) Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br J Pharmacol 157:64–75PubMedPubMedCentralCrossRefGoogle Scholar
  41. Ferreira R, Santos T, Goncalves J, Baltazar G, Ferreira L, Agasse F, Bernardino L (2012) Histamine modulates microglia function. J Neuroinflammation 9:90PubMedPubMedCentralCrossRefGoogle Scholar
  42. Feusner JD, Hembacher E, Phillips KA (2009) The mouse who couldn’t stop washing: pathologic grooming in animals and humans. CNS Spectr 14:503–513PubMedPubMedCentralCrossRefGoogle Scholar
  43. Frick LR, Pittenger C (2017) Microglial dysregulation in OCD, Tourette syndrome, and PANDAS. J Immunol Res 2016:8606057Google Scholar
  44. Frick L, Rapanelli M, Abbasi E, Ohtsu H, Pittenger C (2016) Histamine regulation of microglia: gene-environment interaction in the regulation of central nervous system inflammation. Brain Behav Immun 57:326–337PubMedCrossRefGoogle Scholar
  45. Fried I, Katz A, McCarthy G, Sass KJ, Williamson P, Spencer SS, Spencer DD (1991) Functional organization of human supplementary motor cortex studied by electrical stimulation. J Neurosci 11:3656–3666PubMedGoogle Scholar
  46. Gallezot JD, Planeta B, Nabulsi N, Palumbo D, Li X, Liu J, Rowinski C, Chidsey K, Labaree D, Ropchan J et al (2016) Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746. J Cereb Blood Flow Metab [Epub ahead of print]Google Scholar
  47. Geschwind DH, State MW (2015) Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol 14:1109–1120PubMedPubMedCentralCrossRefGoogle Scholar
  48. Girault JA (2012) Integrating neurotransmission in striatal medium spiny neurons. Adv Exp Med Biol 970:407–429PubMedCrossRefGoogle Scholar
  49. Godar SC, Mosher LJ, Di Giovanni G, Bortolato M (2014) Animal models of tic disorders: a translational perspective. J Neurosci Methods 238:54–69PubMedPubMedCentralCrossRefGoogle Scholar
  50. Greer JM, Capecchi MR (2002) Hoxb8 is required for normal grooming behavior in mice. Neuron 33:23–34PubMedCrossRefGoogle Scholar
  51. Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous system. Physiol Rev 88:1183–1241PubMedCrossRefGoogle Scholar
  52. Halpert AG, Olmstead MC, Beninger RJ (2002) Mechanisms and abuse liability of the anti-histamine dimenhydrinate. Neurosci Biobehav Rev 26:61–67PubMedCrossRefGoogle Scholar
  53. Hampson M, Tokoglu F, King RA, Constable RT, Leckman JF (2009) Brain areas coactivating with motor cortex during chronic motor tics and intentional movements. Biol Psychiatry 65:594–599PubMedCrossRefGoogle Scholar
  54. Hikosaka O, Takikawa Y, Kawagoe R (2000) Role of the basal ganglia in the control of purposive saccadic eye movements. Physiol Rev 80:953–978PubMedGoogle Scholar
  55. Hirschtritt ME, Lee PC, Pauls DL, Dion Y, Grados MA, Illmann C, King RA, Sandor P, McMahon WM, Lyon GJ et al (2015) Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in Tourette syndrome. JAMA Psychiat 72:325–333CrossRefGoogle Scholar
  56. Hoenig K, Hochrein A, Quednow BB, Maier W, Wagner M (2005) Impaired prepulse inhibition of acoustic startle in obsessive-compulsive disorder. Biol Psychiatry 57:1153–1158PubMedCrossRefGoogle Scholar
  57. Iida T, Yoshikawa T, Matsuzawa T, Naganuma F, Nakamura T, Miura Y, Mohsen AS, Harada R, Iwata R, Yanai K (2015) Histamine H3 receptor in primary mouse microglia inhibits chemotaxis, phagocytosis, and cytokine secretion. Glia 63:1213–1225PubMedCrossRefGoogle Scholar
  58. Insel TR, Cuthbert BN (2015) Brain disorders? Precisely. Science 348:499–500PubMedCrossRefGoogle Scholar
  59. Iversen SD, Creese I (1975) Behavioral correlates of dopaminergic supersensitivity. Adv Neurol 9:81–92PubMedGoogle Scholar
  60. Kalanithi PS, Zheng W, Kataoka Y, DiFiglia M, Grantz H, Saper CB, Schwartz ML, Leckman JF, Vaccarino FM (2005) Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proc Natl Acad Sci U S A 102:13307–13312PubMedPubMedCentralCrossRefGoogle Scholar
  61. Kalueff AV, Stewart AM, Song C, Berridge KC, Graybiel AM, Fentress JC (2016) Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci 17:45–59PubMedCrossRefGoogle Scholar
  62. Karagiannidis I, Dehning S, Sandor P, Tarnok Z, Rizzo R, Wolanczyk T, Madruga-Garrido M, Hebebrand J, Nothen MM, Lehmkuhl G et al (2013) Support of the histaminergic hypothesis in Tourette syndrome: association of the histamine decarboxylase gene in a large sample of families. J Med Genet 50:760–764PubMedCrossRefGoogle Scholar
  63. Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman JF, Vaccarino FM (2010) Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. J Comp Neurol 518:277–291PubMedPubMedCentralCrossRefGoogle Scholar
  64. Katayama K, Yamada K, Ornthanalai VG, Inoue T, Ota M, Murphy NP, Aruga J (2010) Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities. Mol Psychiatry 15:177–184PubMedCrossRefGoogle Scholar
  65. Kohl S, Heekeren K, Klosterkotter J, Kuhn J (2013) Prepulse inhibition in psychiatric disorders – apart from schizophrenia. J Psychiatr Res 47:445–452PubMedCrossRefGoogle Scholar
  66. Kumar A, Williams MT, Chugani HT (2015) Evaluation of basal ganglia and thalamic inflammation in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and Tourette syndrome: a positron emission tomographic (PET) study using 11C-[R]-PK11195. J Child Neurol 30:749–756PubMedCrossRefGoogle Scholar
  67. Leckman JF (2002) Tourette’s syndrome. Lancet 360:1577–1586PubMedCrossRefGoogle Scholar
  68. Leckman JF, Bloch MH, Smith ME, Larabi D, Hampson M (2010) Neurobiological substrates of Tourette’s disorder. J Child Adolesc Psychopharmacol 20:237–247PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lennington JB, Coppola G, Kataoka-Sasaki Y, Fernandez TV, Palejev D, Li Y, Huttner A, Pletikos M, Sestan N, Leckman JF et al (2016) Transcriptome analysis of the human striatum in Tourette syndrome. Biol Psychiatry 79:372–382PubMedCrossRefGoogle Scholar
  70. Lyon M, Robbins TW (1975) The action of central nervous system stimuland drugs: a general theory concerning amphetamine effects. In: Essmann WB, Valzelli L (eds) Current developments in psychopharmacology. Spectrum, New York, NY, pp 80–163Google Scholar
  71. Maia TV, Cooney RE, Peterson BS (2008) The neural bases of obsessive-compulsive disorder in children and adults. Dev Psychopathol 20:1251–1283PubMedPubMedCentralCrossRefGoogle Scholar
  72. Matuskey D, Gaiser EC, Gallezot JD, Angarita GA, Pittman B, Nabulsi N, Ropchan J, MaCleod P, Cosgrove KP, Ding YS et al (2015) A preliminary study of dopamine D2/3 receptor availability and social status in healthy and cocaine dependent humans imaged with [(11)C](+)PHNO. Drug Alcohol Depend 154:167–173PubMedPubMedCentralCrossRefGoogle Scholar
  73. McCairn KW, Bronfeld M, Belelovsky K, Bar-Gad I (2009) The neurophysiological correlates of motor tics following focal striatal disinhibition. Brain 132:2125–2138PubMedCrossRefGoogle Scholar
  74. Mink JW (2001) Basal ganglia dysfunction in Tourette’s syndrome: a new hypothesis. Pediatr Neurol 25:190–198PubMedCrossRefGoogle Scholar
  75. Mink JW (2003) The basal ganglia and involuntary movements: impaired inhibition of competing motor patterns. Arch Neurol 60:1365–1368PubMedCrossRefGoogle Scholar
  76. Moreno E, Hoffmann H, Gonzalez-Sepulveda M, Navarro G, Casado V, Cortes A, Mallol J, Vignes M, McCormick PJ, Canela EI et al (2011) Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway. J Biol Chem 286:5846–5854PubMedCrossRefGoogle Scholar
  77. Morisset S, Rouleau A, Ligneau X, Gbahou F, Tardivel-Lacombe J, Stark H, Schunack W, Ganellin CR, Schwartz JC, Arrang JM (2000) High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature 408:860–864PubMedCrossRefGoogle Scholar
  78. Nordstrom EJ, Burton FH (2002) A transgenic model of comorbid Tourette’s syndrome and obsessive-compulsive disorder circuitry. Mol Psychiatry 7(617–625):524CrossRefGoogle Scholar
  79. Ohtsu H (2010) Histamine synthesis and lessons learned from histidine decarboxylase deficient mice. Adv Exp Med Biol 709:21–31PubMedCrossRefGoogle Scholar
  80. Ohtsu H, Tanaka S, Terui T, Hori Y, Makabe-Kobayashi Y, Pejler G, Tchougounova E, Hellman L, Gertsenstein M, Hirasawa N et al (2001) Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett 502:53–56PubMedCrossRefGoogle Scholar
  81. Olah M, Biber K, Vinet J, Boddeke HW (2011) Microglia phenotype diversity. CNS Neurol Disord Drug Targets 10:108–118PubMedCrossRefGoogle Scholar
  82. Oleson EB, Ferris MJ, Espana RA, Harp J, Jones SR (2012) Effects of the histamine H(1) receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward. Eur J Pharmacol 683:161–165PubMedPubMedCentralCrossRefGoogle Scholar
  83. Panula P, Nuutinen S (2013) The histaminergic network in the brain: basic organization and role in disease. Nat Rev Neurosci 14:472–487PubMedCrossRefGoogle Scholar
  84. Panula P, Yang HY, Costa E (1984) Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci U S A 81:2572–2576PubMedPubMedCentralCrossRefGoogle Scholar
  85. Payer DE, Behzadi A, Kish SJ, Houle S, Wilson AA, Rusjan PM, Tong J, Selby P, George TP, McCluskey T et al (2014) Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO. Neuropsychopharmacology 39:311–318PubMedCrossRefGoogle Scholar
  86. Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G (2011) Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472:437–442PubMedPubMedCentralCrossRefGoogle Scholar
  87. Pittenger C (2014) Animal models of Tourette syndrome and obsessive-compulsive disorder. In: LeDoux M (ed) Animal models of movement disorders. Elsevier; Academic Press, San Diego, CA, pp 748–766Google Scholar
  88. Pittenger C (2017) The neurobiology of tic disorders and obsessive-compulsive disorder: human and animal studies. In: Nestler E, Buxbaum J, Sklar P, Charney DS (eds) Charney and Nestler’s neurobiology of mental illness. Oxford University Press, New York, NYGoogle Scholar
  89. Pittenger C, Bloch MH, Williams K (2011) Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther 132:314–332PubMedPubMedCentralCrossRefGoogle Scholar
  90. Pittenger C, Dulawa S, Thompson SL (2017) Animal models of OCD: a conceptual framework. In: Pittenger C (ed) Obsessive-compulsive disorder: phenomenology, pathophysiology, and treatment. Oxford University Press, New York, NYGoogle Scholar
  91. Pogorelov V, Xu M, Smith HR, Buchanan GF, Pittenger C (2015) Corticostriatal interactions in the generation of tic-like behaviors after local striatal inhibition. Exp Neurol 265:122–128PubMedPubMedCentralCrossRefGoogle Scholar
  92. Rabiner EA, Slifstein M, Nobrega J, Plisson C, Huiban M, Raymond R, Diwan M, Wilson AA, McCormick P, Gentile G et al (2009) In vivo quantification of regional dopamine-D3 receptor binding potential of (+)-PHNO: studies in non-human primates and transgenic mice. Synapse 63:782–793PubMedCrossRefGoogle Scholar
  93. Rapanelli M, Pittenger C (2016) Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions. Neuropharmacology 106:85–90PubMedCrossRefGoogle Scholar
  94. Rapanelli M, Frick LR, Pogorelov V, Ota KT, Abbasi E, Ohtsu H, Pittenger C (2014) Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome. Eur Neuropsychopharmacol 24:1896–1906PubMedPubMedCentralCrossRefGoogle Scholar
  95. Rapanelli M, Frick LR, Horn KD, Schwarcz RC, Pogorelov V, Nairn AC, Pittenger C (2016) The histamine H3 receptor differentially modulates mitogen-activated protein kinase (MAPK) and Akt signaling in striatonigral and striatopallidal neurons. J Biol Chem 291:21042–21052PubMedCrossRefGoogle Scholar
  96. Rapanelli M, Frick L, Pogorelov V, Ohtsu H, Bito H, Pittenger C (2017) Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders. Transl Psychiatry 7(1):e1013Google Scholar
  97. Robertson MM, Eapen V, Cavanna AE (2009) The international prevalence, epidemiology, and clinical phenomenology of Tourette syndrome: a cross-cultural perspective. J Psychosom Res 67:475–483PubMedCrossRefGoogle Scholar
  98. Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, Matuskey D, Lee JY, O’Connor KC, Huang Y et al (2015) Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci U S A 112:12468–12473PubMedPubMedCentralCrossRefGoogle Scholar
  99. Scahill L, Tanner C, Dure L (2001) The epidemiology of tics and Tourette syndrome in children and adolescents. Adv Neurol 85:261–271PubMedGoogle Scholar
  100. Scharf JM, Miller LL, Mathews CA, Ben-Shlomo Y (2012) Prevalence of Tourette syndrome and chronic tics in the population-based Avon longitudinal study of parents and children cohort. J Am Acad Child Adolesc Psychiatry 51(192–201):e195Google Scholar
  101. Scharf JM, Yu D, Mathews CA, Neale BM, Stewart SE, Fagerness JA, Evans P, Gamazon E, Edlund CK, Service SK et al (2013) Genome-wide association study of Tourette’s syndrome. Mol Psychiatry 18:721–728PubMedCrossRefGoogle Scholar
  102. Schlicker E, Malinowska B, Kathmann M, Gothert M (1994) Modulation of neurotransmitter release via histamine H3 heteroreceptors. Fundam Clin Pharmacol 8:128–137PubMedCrossRefGoogle Scholar
  103. Schneider EH, Seifert R (2016) The histamine H4-receptor and the central and peripheral nervous system: a critical analysis of the literature. Neuropharmacology 106:116–128PubMedCrossRefGoogle Scholar
  104. Schneider EH, Neumann D, Seifert R (2014) Modulation of behavior by the histaminergic system: lessons from HDC-, H3R- and H4R-deficient mice. Neurosci Biobehav Rev 47:101–121PubMedCrossRefGoogle Scholar
  105. Shmelkov SV, Hormigo A, Jing D, Proenca CC, Bath KG, Milde T, Shmelkov E, Kushner JS, Baljevic M, Dincheva I et al (2010) Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat Med 16:598–602. 591 pp following 602PubMedPubMedCentralCrossRefGoogle Scholar
  106. Singer HS, Wong DF, Brown JE, Brandt J, Krafft L, Shaya E, Dannals RF, Wagner HN Jr (1992) Positron emission tomography evaluation of dopamine D-2 receptors in adults with Tourette syndrome. Adv Neurol 58:233–239PubMedGoogle Scholar
  107. Stanwood GD, Lucki I, McGonigle P (2000) Differential regulation of dopamine D2 and D3 receptors by chronic drug treatments. J Pharmacol Exp Ther 295:1232–1240PubMedGoogle Scholar
  108. Stillman AA, Krsnik Z, Sun J, Rasin MR, State MW, Sestan N, Louvi A (2009) Developmentally regulated and evolutionarily conserved expression of SLITRK1 in brain circuits implicated in Tourette syndrome. J Comp Neurol 513:21–37PubMedPubMedCentralCrossRefGoogle Scholar
  109. Suzuki T, Mori T, Tsuji M, Nomura M, Misawa M, Onodera K (1999) Evaluation of the histamine H1-antagonist-induced place preference in rats. Jpn J Pharmacol 81:332–338PubMedCrossRefGoogle Scholar
  110. Swerdlow NR, Karban B, Ploum Y, Sharp R, Geyer MA, Eastvold A (2001) Tactile prepuff inhibition of startle in children with Tourette’s syndrome: in search of an “fMRI-friendly” startle paradigm. Biol Psychiatry 50:578–585PubMedCrossRefGoogle Scholar
  111. Tziortzi AC, Searle GE, Tzimopoulou S, Salinas C, Beaver JD, Jenkinson M, Laruelle M, Rabiner EA, Gunn RN (2011) Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy. Neuroimage 54:264–277PubMedCrossRefGoogle Scholar
  112. Volkow ND, Wang GJ, Kollins SH, Wigal TL, Newcorn JH, Telang F, Fowler JS, Zhu W, Logan J, Ma Y et al (2009) Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA 302:1084–1091PubMedPubMedCentralCrossRefGoogle Scholar
  113. Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD, Feliciano C, Chen M, Adams JP, Luo J et al (2007) Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448:894–900PubMedPubMedCentralCrossRefGoogle Scholar
  114. Williams KA, Swedo SE (2015) Post-infectious autoimmune disorders: Sydenham’s chorea, PANDAS and beyond. Brain Res 1617:144–154PubMedCrossRefGoogle Scholar
  115. Wong DF, Brasic JR, Singer HS, Schretlen DJ, Kuwabara H, Zhou Y, Nandi A, Maris MA, Alexander M, Ye W et al (2008) Mechanisms of dopaminergic and serotonergic neurotransmission in Tourette syndrome: clues from an in vivo neurochemistry study with PET. Neuropsychopharmacology 33:1239–1251PubMedCrossRefGoogle Scholar
  116. Xu M, Kobets A, Du JC, Lennington J, Li L, Banasr M, Duman RS, Vaccarino FM, DiLeone RJ, Pittenger C (2015a) Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proc Natl Acad Sci U S A 112:893–898PubMedPubMedCentralCrossRefGoogle Scholar
  117. Xu M, Li L, Ohtsu H, Pittenger C (2015b) Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear. Neurosci Lett 595:50–53PubMedPubMedCentralCrossRefGoogle Scholar
  118. Xu M, Li L, Pittenger C (2016) Ablation of fast-spiking neurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming. Neuroscience 324:321–329PubMedCrossRefGoogle Scholar
  119. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A, Gozzi A, Ragozzino D et al (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 17:400–406PubMedCrossRefGoogle Scholar
  120. Zimmermann P, Privou C, Huston JP (1999) Differential sensitivity of the caudal and rostral nucleus accumbens to the rewarding effects of a H1-histaminergic receptor blocker as measured with place-preference and self-stimulation behavior. Neuroscience 94:93–103PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Departments of Psychiatry and Psychology, Yale Child Study Center, and Interdepartmental Neuroscience ProgramYale University School of MedicineNew HavenUSA

Personalised recommendations