Skip to main content

Advertisement

SpringerLink
Log in

Abnormal Expression Pattern of Notch Receptors, Ligands, and Downstream Effectors in the Dorsolateral Prefrontal Cortex and Amygdala of Suicidal Victims

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Recent studies have associated alterations of neuronal plasticity in specific brain areas with suicidal behavior. The Notch signaling pathway plays a relevant role in the control of stem cell maintenance, cell migration, and neuronal plasticity. In the present study, the gene expression of the four Notch receptors (NOTCH1–4), the five canonical ligands (DLL1, DLL3, DLL4, JAGGED1, and JAGGED2), the two non-canonical ligands (DLK1 and DLK2), and the transcription factors (HES1, HEY1, and HEY2) were measured in the dorsolateral prefrontal cortex (DLPFC) and amygdala (AMY) of suicide victims (S; n = 13 males, with no clinical psychiatric history and non-treated with anxiolytic or antidepressant drugs) and their corresponding controls (C; n = 13 males) by real-time PCR. The results revealed a reduction of NOTCH2 and NOTCH1, NOTCH3, and NOTCH4 gene expression in the DLPFC and AMY of S compared with C, respectively. DLL1 levels were increased in the DLPFC and decreased in the AMY, whereas DLL4, JAGGED1, and JAGGED2 were significantly decreased in the regions analyzed. DLK1 was reduced in the AMY, whereas no changes were observed in the DLPFC and in DLK2 expression levels in any of the regions analyzed. HES1 was significantly reduced in both brain regions from S, whereas there were no significant changes in HEY1 and HEY2. This study provides evidence suggesting that the Notch signaling pathway could be a potential key target in the treatment of suicidal behaviors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. WHO. Suicide. Introduction. http://www.who.int/mental_health/media/en/382.pdf. 2012

  2. Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN (2003) Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 60(8):804–815

    Article  CAS  PubMed  Google Scholar 

  3. Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R (2005) Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 136(1–2):29–37

    Article  CAS  PubMed  Google Scholar 

  4. Dwivedi Y, Mondal AC, Rizavi HS, Conley RR (2005) Suicide brain is associated with decreased expression of neurotrophins. Biol Psychiatry 58(4):315–324

    Article  CAS  PubMed  Google Scholar 

  5. Kim YK, Lee HP, Won SD, Park EY, Lee HY, Lee BH et al (2007) Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuropsychopharmacol Biol Psychiatry 31(1):78–85

    Article  CAS  PubMed  Google Scholar 

  6. Sarchiapone M, Carli V, Roy A, Iacoviello L, Cuomo C, Latella MC et al (2008) Association of polymorphism (Val66Met) of brain-derived neurotrophic factor with suicide attempts in depressed patients. Neuropsychobiology 57(3):139–145

    Article  CAS  PubMed  Google Scholar 

  7. Perroud N, Courtet P, Vincze I, Jaussent I, Jollant F, Bellivier F et al (2008) Interaction between BDNF Val66Met and childhood trauma on adult's violent suicide attempt. Genes Brain Behav 7(3):314–322

    Article  CAS  PubMed  Google Scholar 

  8. Pregelj P, Nedic G, Paska AV, Zupanc T, Nikolac M, Balazic J et al (2011) The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide. J Affect Disord 128(3):287–290

    Article  CAS  PubMed  Google Scholar 

  9. Keller S, Sarchiapone M, Zarrilli F, Videtic A, Ferraro A, Carli V et al (2010) Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch Gen Psychiatry 67(3):258–267

    Article  CAS  PubMed  Google Scholar 

  10. Soloff PH, Pruitt P, Sharma M, Radwan J, White R, Diwadkar VA (2012) Structural brain abnormalities and suicidal behavior in borderline personality disorder. J Psychiatr Res 46(4):516–525

    Article  PubMed Central  PubMed  Google Scholar 

  11. Desmyter S, van Heeringen C, Audenaert K (2011) Structural and functional neuroimaging studies of the suicidal brain. Prog Neuropsychopharmacol Biol Psychiatry 35(4):796–808

    Article  CAS  PubMed  Google Scholar 

  12. Hwang JP, Lee TW, Tsai SJ, Chen TJ, Yang CH, Lirng JF et al (2010) Cortical and subcortical abnormalities in late-onset depression with history of suicide attempts investigated with MRI and voxel-based morphometry. J Geriatr Psychiatry Neurol 23(3):171–184

    Article  PubMed  Google Scholar 

  13. Imayoshi I, Kageyama R (2011) The role of Notch signaling in adult neurogenesis. Mol Neurobiol 44(1):7–12

    Article  CAS  PubMed  Google Scholar 

  14. Kageyama R, Ohtsuka T (1999) The Notch-Hes pathway in mammalian neural development. Cell Res 9(3):179–188

    Article  CAS  PubMed  Google Scholar 

  15. D'Souza B, Meloty-Kapella L, Weinmaster G (2010) Canonical and non-canonical Notch ligands. Curr Top Dev Biol 92:73–129

    Article  PubMed  Google Scholar 

  16. Kopan R (2012) Notch signaling. Cold Spring Harb Perspect Biol 4(10)

  17. Borggrefe T, Liefke R (2012) Fine-tuning of the intracellular canonical Notch signaling pathway. Cell Cycle 11(2):264–276

    Article  CAS  PubMed  Google Scholar 

  18. Kageyama R, Ohtsuka T, Kobayashi T (2008) Roles of Hes genes in neural development. Develop Growth Differ 50(Suppl 1):S97–S103

    Article  CAS  Google Scholar 

  19. Fischer A, Gessler M (2007) Delta-Notch–and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 35(14):4583–4596

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Sanchez-Solana B, Nueda ML, Ruvira MD, Ruiz-Hidalgo MJ, Monsalve EM, Rivero S et al (2011) The EGF-like proteins DLK1 and DLK2 function as inhibitory non-canonical ligands of NOTCH1 receptor that modulate each other's activities. Biochim Biophys Acta 1813(6):1153–1164

    Article  CAS  PubMed  Google Scholar 

  21. Arendt T (2003) Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the 'Dr. Jekyll and Mr. Hyde concept' of Alzheimer's disease or the yin and yang of neuroplasticity. Prog Neurobiol 71(2–3):83–248

    Article  PubMed  Google Scholar 

  22. Ren X, Rizavi HS, Khan MA, Dwivedi Y, Pandey GN (2012) Altered Wnt signalling in the teenage suicide brain: focus on glycogen synthase kinase-3beta and beta-catenin. Int J Neuropsychopharmacol 1–11

  23. Shayevitz C, Cohen OS, Faraone SV, Glatt SJ (2012) A re-review of the association between the NOTCH4 locus and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 159B(5):477–483

    Article  PubMed  Google Scholar 

  24. Vermeulen J, De Preter K, Lefever S, Nuytens J, De Vloed F, Derveaux S (2012) Measurable impact of RNA quality on gene expression results from quantitative PCR. Nucleic Acids Res 39(9):e63

    Article  Google Scholar 

  25. Klempan TA, Ernst C, Deleva V, Labonte B, Turecki G (2009) Characterization of QKI gene expression, genetics, and epigenetics in suicide victims with major depressive disorder. Biol Psychiatry 66(9):824–831

    Article  CAS  PubMed  Google Scholar 

  26. Sakamoto M, Hirata H, Ohtsuka T, Bessho Y, Kageyama R (2003) The basic helix-loop-helix genes Hesr1/Hey1 and Hesr2/Hey2 regulate maintenance of neural precursor cells in the brain. J Biol Chem 278(45):44808–44815

    Article  CAS  PubMed  Google Scholar 

  27. Dwivedi Y (2012) Brain-Derived Neurotrophic Factor in Suicide Pathophysiology. In: Dwivedi Y (ed). The Neurobiological Basis of Suicide: Boca Raton (FL)

  28. Torres-Platas SG, Hercher C, Davoli MA, Maussion G, Labonte B, Turecki G et al (2011) Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology: Off Publ Am Coll Neuropsychopharmacol 36(13):2650–2658

    Article  Google Scholar 

  29. Dwivedi Y (2012) The Neurobiological Basis of Suicide. Chapter 8. Brain-Derived Neurotrophic Factor in Suicide Pathophysiology. CRC Press, Boca Raton

    Google Scholar 

  30. Snyder JL, Kearns CA, Appel B (2012) Fbxw7 regulates Notch to control specification of neural precursors for oligodendrocyte fate. Neural Develop 7:15

    Article  CAS  Google Scholar 

  31. Alberi L, Liu S, Wang Y, Badie R, Smith-Hicks C, Wu J et al (2011) Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. Neuron 69(3):437–444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Ferron SR, Charalambous M, Radford E, McEwen K, Wildner H, Hind E et al (2011) Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475(7356):381–385

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Gomez-Duran EL, Martin-Fumado C, Hurtado-Ruiz G (2012) Clinical and epidemiological aspects of suicide in patients with schizophrenia. Actas Esp Psiquiatr 40(6):333–345

    PubMed  Google Scholar 

  34. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383(6602):707–710

    Article  CAS  PubMed  Google Scholar 

  35. Arboleda-Velasquez JF, Manent J, Lee JH, Tikka S, Ospina C, Vanderburg CR et al (2011) Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease. Proc Natl Acad Sci U S A 108(21):E128–E135

    Article  PubMed Central  PubMed  Google Scholar 

  36. Meng H, Zhang X, Yu G, Lee SJ, Chen YE, Prudovsky I et al (2012) Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3. PloS one 7(9):e44964

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Alasaari JS, Lagus M, Ollila HM, Toivola A, Kivimaki M, Vahtera J et al (2012) Environmental stress affects DNA methylation of a CpG rich promoter region of serotonin transporter gene in a nurse cohort. PloS one 7(9):e45813

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Piazzi G, Fini L, Selgrad M, Garcia M, Daoud Y, Wex T et al (2011) Epigenetic regulation of Delta-Like1 controls Notch1 activation in gastric cancer. Oncotarget 2(12):1291–1301

    PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from Ministry of Science and Innovation (SAF 2008–01106, RETICS RD12/0028/0019, and FEDER) and Ministry of Health (PNSD 2007/061). FN is a postdoctoral fellow of the RETICS RD12/0028/0019. We thank Analía Rico for their excellent technical assistance.

Conflict of interest

All authors state that they have no biochemical financial interest or potential conflicts of interest.

Author information

Authors and Affiliations

  1. Facultad de Medicina, Universidad de Castilla-La Mancha/Centro Regional de Investigaciones Biomédicas (CRIB), Albacete, Spain

    Eva M. Monsalve & Jorge Laborda

  2. Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550, Alicante, Spain

    María S. García-Gutiérrez, Francisco Navarrete & Jorge Manzanares

  3. Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain

    María S. García-Gutiérrez, Francisco Navarrete & Jorge Manzanares

  4. Instituto de Medicina Legal, Avda. Aguilera 53, 03007, Alicante, Spain

    Salvador Giner

Authors
  1. Eva M. Monsalve
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María S. García-Gutiérrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francisco Navarrete
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Salvador Giner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jorge Laborda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jorge Manzanares
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jorge Manzanares.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Monsalve, E.M., García-Gutiérrez, M.S., Navarrete, F. et al. Abnormal Expression Pattern of Notch Receptors, Ligands, and Downstream Effectors in the Dorsolateral Prefrontal Cortex and Amygdala of Suicidal Victims. Mol Neurobiol 49, 957–965 (2014). https://doi.org/10.1007/s12035-013-8570-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-013-8570-z

Keywords

Search

Navigation