OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency

Molecular Psychiatry

Volumn 23, Issue 2, 2018, Pages 444-458

  Ullrich, M ^a   Weber, M ^b   Post, A M ^a,b   Popp, S ^a   Grein, J ^a   Zechner, M ^a   Guerrero Gonzalez H ^a   Kreis, A ^a   Schmitt, A G ^a   Uceyler N ^a   Lesch, K P ^a,c   Schuh, K ^a  

^a UNIVERSITY OF WÜRZBURG   (Germany)

^b GOETHE UNIVERSITY   (Germany)

^c MAASTRICHT UNIVERSITY   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR RECEPTOR; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; RAS PROTEIN; SELUMETINIB; SPROUTY PROTEIN; SPROUTY RELATED PROTEIN WITH EVH1 DOMAIN 2 PROTEIN; UNCLASSIFIED DRUG; FLUOXETINE; MITOGEN ACTIVATED PROTEIN KINASE; REPRESSOR PROTEIN; SPRED2 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; ELECTROPHYSIOLOGY; EMBRYO; ENZYME ACTIVATION; ENZYME REPRESSION; GENETIC TRANSCRIPTION; IN VIVO STUDY; LATERAL AMYGDALA; LIMIT OF QUANTITATION; MALE; MAPK SIGNALING; MOUSE; NONHUMAN; OBSESSIVE COMPULSIVE DISORDER; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; SYNAPTIC TRANSMISSION; THALAMOCORTICAL TRACT; UPREGULATION; AMYGDALA; ANIMAL; COMPULSION; CORPUS STRIATUM; GENETICS; KNOCKOUT MOUSE; METABOLISM; NERVE CELL; OBSESSION; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION; SYNAPSE; THALAMUS;

AMYGDALA; ANIMALS; COMPULSIVE BEHAVIOR; CORPUS STRIATUM; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; FLUOXETINE; MAP KINASE SIGNALING SYSTEM; MICE; MICE, KNOCKOUT; NEURONS; OBSESSIVE BEHAVIOR; OBSESSIVE-COMPULSIVE DISORDER; RECEPTOR, TRKB; REPRESSOR PROTEINS; SIGNAL TRANSDUCTION; SYNAPSES; SYNAPTIC TRANSMISSION; THALAMUS;

EID: 85008627618     PISSN: 13594184     EISSN: 14765578     Source Type: Journal    
DOI: 10.1038/mp.2016.232     Document Type: Article

References (78)

1. Leckman JF, Grice DE, Boardman J, Zhang H, Vitale A, Bondi C et al. Symptoms of obsessive-compulsive disorder. Am J Psychiatry 1997; 154: 911-917.
2. Miguel EC, Leckman JF, Rauch S, do Rosario-Campos MC, Hounie AG, Mercadante MT et al. Obsessive-compulsive disorder phenotypes: implications for genetic studies. Mol Psychiatry 2005; 10: 258-275.
3. Fineberg NA, Potenza MN, Chamberlain SR, Berlin HA, Menzies L, Bechara A et al. Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review. Neuropsychopharmacology 2010; 35: 591-604.
4. Browne HA, Gair SL, Scharf JM, Grice DE. Genetics of obsessive-compulsive disorder and related disorders. Psychiatr Clin North Am 2014; 37: 319-335.
5. Graybiel AM, Rauch SL. Toward a neurobiology of obsessive-compulsive disorder. Neuron 2000; 28: 343-347.
6. Aouizerate B, Guehl D, Cuny E, Rougier A, Bioulac B, Tignol J et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol 2004; 72: 195-221.
7. Ahmari SE, Spellman T, Douglass NL, Kheirbek MA, Simpson HB, Deisseroth K et al. Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science (New York, NY) 2013; 340: 1234-1239.
8. Janak PH, Tye KM. From circuits to behaviour in the amygdala. Nature 2015; 517: 284-292.
9. Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol Psychiatry 2001; 6: 13-34.
10. Milad MR, Rauch SL. Obsessive-compulsive disorder: beyond segregated corticostriatal pathways. Trends Cogn Sci 2012; 16: 43-51.
11. Taylor S. Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies. Mol Psychiatry 2013; 18: 799-805.
12. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001; 24: 677-736.
13. Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 2003; 72: 609-642.
14. Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64: 238-258.
15. Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 2009; 5: 311-322.
16. Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M. Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet 2003; 73: 370-376.
17. Hemmings SM, Kinnear CJ, Van der Merwe L, Lochner C, Corfield VA, Moolman-Smook JC et al. Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD). World J Biol Psychiatry 2008; 9: 126-134.
18. Oliveira-Maia AJ, Castro-Rodrigues P. Brain-derived neurotrophic factor: a biomarker for obsessive-compulsive disorder? Front Neurosci 2015; 9: 134.
19. Alonso P, Gratacos M, Menchon JM, Saiz-Ruiz J, Segalas C, Baca-Garcia E et al. Extensive genotyping of the BDNF and NTRK2 genes define protective haplotypes against obsessive-compulsive disorder. Biol Psychiatry 2008; 63: 619-628.
20. Olsen D, Kaas M, Schwartz O, Nykjaer A, Glerup S. Loss of BDNF or its receptors in three mouse models has unpredictable consequences for anxiety and fear acquisition. Learn Mem 2013; 20: 499-504.
21. Guiton M, Gunn-Moore FJ, Stitt TN, Yancopoulos GD, Tavare JM. Identification of in vivo brain-derived neurotrophic factor-stimulated autophosphorylation sites on the TrkB receptor tyrosine kinase by site-directed mutagenesis. J Biol Chem 1994; 269: 30370-30377.
22. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 2002; 12: 9-18.
23. Wakioka T, Sasaki A, Kato R, Shouda T, Matsumoto A, Miyoshi K et al. Spred is a Sprouty-related suppressor of Ras signalling. Nature 2001; 412: 647-651.
24. King JA, Straffon AF, D'Abaco GM, Poon CL, I ST, Smith CM et al. Distinct requirements for the Sprouty domain for functional activity of Spred proteins. Biochem J 2005; 388(Pt 2): 445-454.
25. Bundschu K, Walter U, Schuh K. Getting a first clue about SPRED functions. Bioessays 2007; 29: 897-907.
26. Bundschu K, Gattenlohner S, Knobeloch KP, Walter U, Schuh K. Tissue-specific Spred-2 promoter activity characterized by a gene trap approach. Gene Expr Patterns 2006; 6: 247-255.
27. Engelhardt CM, Bundschu K, Messerschmitt M, Renne T, Walter U, Reinhard M et al. Expression and subcellular localization of Spred proteins in mouse and human tissues. Histochem Cell Biol 2004; 122: 527-538.
28. Phoenix TN, Temple S. Spred1, a negative regulator of Ras-MAPK-ERK, is enriched in CNS germinal zones, dampens NSC proliferation, and maintains ventricular zone structure. Genes Dev 2010; 24: 45-56.
29. Mardakheh FK, Yekezare M, Machesky LM, Heath JK. Spred2 interaction with the late endosomal protein NBR1 down-regulates fibroblast growth factor receptor signaling. J Cell Biol 2009; 187: 265-277.
30. Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 2007; 39: 1120-1126.
31. Denayer E, Ahmed T, Brems H, Van Woerden G, Borgesius NZ, Callaerts-Vegh Z et al. Spred1 is required for synaptic plasticity and hippocampus-dependent learning. J Neurosci 2008; 28: 14443-14449.
32. Inoue H, Kato R, Fukuyama S, Nonami A, Taniguchi K, Matsumoto K et al. Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. J Exp Med 2005; 201: 73-82.
33. Ullrich M, Bundschu K, Benz PM, Abesser M, Freudinger R, Fischer T et al. Identification of SPRED2 (Sprouty-related Protein with EVH1 Domain 2) as a Negative Regulator of the Hypothalamic-Pituitary-Adrenal Axis. J Biol Chem 2011; 286: 9477-9488.
34. Bundschu K, Knobeloch KP, Ullrich M, Schinke T, Amling M, Engelhardt CM et al. Gene disruption of Spred-2 causes dwarfism. J Biol Chem 2005; 280: 28572-28580.
35. Ullrich M, Schuh K. Gene trap: knockout on the fast lane. Methods Mol Biol (Clifton, NJ) 2009; 561: 145-159.
36. Faul F, Erdfelder E, Lang AG, Buchner A. G∗Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 2007; 39: 175-191.
37. Post AM, Weyers P, Holzer P, Painsipp E, Pauli P, Wultsch T et al. Gene-environment interaction influences anxiety-like behavior in ethologically based mouse models. Behav Brain Res 2011; 218: 99-105.
38. Bourin M, Hascoet M. The mouse light/dark box test. Eur J Pharmacol 2003; 463: 55-65.
39. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55-63.
40. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988; 32: 77-88.
41. Paxinos G, Franklin KBJ. The Mouse Brain in Stereotaxic Coordinates. Academic Press, 1997.
42. Nietzer SL, Bonn M, Jansen F, Heiming RS, Lewejohann L, Sachser N et al. Serotonin transporter knockout and repeated social defeat stress: impact on neuronal morphology and plasticity in limbic brain areas. Behav Brain Res 2011; 220: 42-54.
43. Chen Y, Boettger MK, Reif A, Schmitt A, Uceyler N, Sommer C. Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice. Mol Pain 2010; 6: 13.
44. Huang GJ, Bannerman D, Flint J. Chronic fluoxetine treatment alters behavior, but not adult hippocampal neurogenesis, in BALB/cJ mice. Mol Psychiatry 2008; 13: 119-121.
45. Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 2007; 448: 894-900.
46. Shmelkov SV, Hormigo A, Jing D, Proenca CC, Bath KG, Milde T et al. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat Med 2010; 16: 598-602, 591p following 602.
47. Bartz JA, Hollander E. Is obsessive-compulsive disorder an anxiety disorder? Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 338-352.
48. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessivecompulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry 2010; 15: 53-63.
49. Stein DJ, Fineberg NA, Bienvenu OJ, Denys D, Lochner C, Nestadt G et al. Should OCD be classified as an anxiety disorder in DSM-V? Depress Anxiety 2010; 27: 495-506.
50. Association AP (ed). Diagnostic and statistical manual of mental disorders. 5th Edition. American Psychiatric Publishing: Arlington, VA, 2013.
51. Findley DB, Leckman JF, Katsovich L, Lin H, Zhang H, Grantz H et al. Development of the Yale Children's Global Stress Index (YCGSI) and its application in children and adolescents ith Tourette's syndrome and obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 2003; 42: 450-457.
52. Toro J, Cervera M, Osejo E, Salamero M. Obsessive-compulsive disorder in childhood and adolescence: a clinical study. J Child Psychol Psychiatry 1992; 33: 1025-1037.
53. Altemus M, Pigott T, Kalogeras KT, Demitrack M, Dubbert B, Murphy DL et al. Abnormalities in the regulation of vasopressin and corticotropin releasing factor secretion in obsessive-compulsive disorder. Arch Gen Psychiatry 1992; 49: 9-20.
54. Kluge M, Schussler P, Kunzel HE, Dresler M, Yassouridis A, Steiger A. Increased nocturnal secretion of ACTH and cortisol in obsessive compulsive disorder. J Psychiatr Res 2007; 41: 928-933.
55. Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev 2008; 32: 525-549.
56. Wood J, Ahmari SE. A framework for understanding the emerging role of corticolimbic-ventral striatal networks in OCD-associated repetitive behaviors. Front Syst Neurosci 2015; 9: 171.
57. Breiter HC, Rauch SL, Kwong KK, Baker JR, Weisskoff RM, Kennedy DN et al. Functional magnetic resonance imaging of symptom provocation in obsessivecompulsive disorder. Arch Gen Psychiatry 1996; 53: 595-606.
58. Albelda N, Joel D. Current animal models of obsessive compulsive disorder: an update. Neuroscience 2012; 211: 83-106.
59. Sudhof TC. The presynaptic active zone. Neuron 2012; 75: 11-25.
60. Kittel RJ, Wichmann C, Rasse TM, Fouquet W, Schmidt M, Schmid A et al. Bruchpilot promotes active zone assembly, Ca2+ channel clustering, and vesicle release. Science (New York, NY) 2006; 312: 1051-1054.
61. Davydova D, Marini C, King C, Klueva J, Bischof F, Romorini S et al. Bassoon specifically controls presynaptic P/Q-type Ca(2+) channels via RIM-binding protein. Neuron 2014; 82: 181-194.
62. Benarroch EE. Metabotropic glutamate receptors: synaptic modulators and therapeutic targets for neurologic disease. Neurology 2008; 70: 964-968.
63. Niswender CM, Conn PJ. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 2010; 50: 295-322.
64. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P et al. Coupling of mGluR/ Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 1999; 23: 583-592.
65. Keith D, El-Husseini A. Excitation control: balancing PSD-95 function at the synapse. Front Mol Neurosci 2008; 1: 4.
66. Steiner P, Higley MJ, Xu W, Czervionke BL, Malenka RC, Sabatini BL. Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity. Neuron 2008; 60: 788-802.
67. Vanderklish PW, Edelman GM. Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons. Proc Natl Acad Sci USA 2002; 99: 1639-1644.
68. Chakravarthy S, Saiepour MH, Bence M, Perry S, Hartman R, Couey JJ et al. Postsynaptic TrkB signaling has distinct roles in spine maintenance in adult visual cortex and hippocampus. Proc Natl Acad Sci USA 2006; 103: 1071-1076.
69. Alonso M, Medina JH, Pozzo-Miller L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 2004; 11: 172-178.
70. Bennett MR, Lagopoulos J. Stress and trauma: BDNF control of dendritic-spine formation and regression. Prog Neurobiol 2014; 112: 80-99.
71. Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci 2009; 10: 423-433.
72. Meng S, Zhang M, Pan W, Li Z, Anderson DH, Zhang S et al. Tyrosines 303/343/353 within the Sprouty-related domain of Spred2 are essential for its interaction with p85 and inhibitory effect on Ras/ERK activation. Int J Biochem Cell Biol 2012; 44: 748-758.
73. Quintanar-Audelo M, Yusoff P, Sinniah S, Chandramouli S, Guy GR. Sprouty-related Ena/VASP homology 1-domain-containing protein (SPRED) 1, a SHP2 substrate in the Ras/ERK pathway. J Biol Chem 2011; 286: 23102-23112.
74. Kelleher RJ 3rd, Govindarajan A, Jung HY, Kang H, Tonegawa S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 2004; 116: 467-479.
75. Cui Y, Costa RM, Murphy GG, Elgersma Y, Zhu Y, Gutmann DH et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 2008; 135: 549-560.
76. Giese KP, Mizuno K. The roles of protein kinases in learning and memory. Learn Mem 2013; 20: 540-552.
77. Bartholomeusz C, Xie X, Pitner MK, Kondo K, Dadbin A, Lee J et al. MEK inhibitor selumetinib (AZD6244; ARRY-142886) prevents lung metastasis in a triple-negative breast cancer xenograft model. Mol Cancer Ther 2015; 14: 2773-2781.
78. Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. J Am Med Assoc 2014; 311: 2397-2405.