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Synaptoproteomics of Existing and new Animal Models of Depression

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Abstract

Depression is a severe and life-threatening psychiatric illness whose pathogenesis is still essentially unknown. Proteomic analysis of synaptic terminals (synaptoproteomics) in animal models of depression is a powerful approach to gain insight into the molecular mechanisms underlying vulnerability to mood disorders and the long-term action of drug treatments. Here, we employed two different animal models of depression, the Learned Helplessness rats (a classical behavioral model of depression) and a new model of depression with gene—environment interaction (Flinders Sensitive Line rats subjected to early life stress). Both animal models were treated with the antidepressant escitalopram. Analysis of their synaptoproteomic profile revealed a number of protein spots differently regulated by basic vulnerability and/or early life stress. Using this approach, we obtained information regarding biomarkers that may represent predictors of pathology or response/resistance to drug treatment, as well as potential targets for novel pharmacological and therapeutic strategies.

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Abbreviations

2D:

Two-dimensional

5-HT1A :

Serotonin 1A receptor

BCA:

Bicinchoninic Acid

CHAPS:

(3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate)

DA:

Dopamine

DAVID:

Database for Annotation, Visualization and Integrated Discovery

ESC:

Escitalopram

FRL:

Flinders sensitive line

FSL:

Flinders resistant line

G × E:

Gene—environment interaction

GO:

Gene Ontology

HC:

Hippocampus

HPA:

Hypothalamic—pituitary—adrenal

IBS:

Inflammatory bowel syndrome

IEF:

Isoelectric focusing

IPA:

Ingenuity pathways analysis

IPG:

Immobilized pH gradient

LH:

Learned helplessness

mRNA:

Messenger RNA

MS:

Maternal separation

nLH:

Non-learned helplessness

NMDA:

N-methyl-D-aspartate

P/FC:

Prefrontal/frontal cortex

pI:

Isoelectric point

PND:

Post natal day

REM:

Random eyes movement

SDS:

Sodium dodecyl sulfate

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

Tris:

Tris(hydroxymethyl)aminomethane

Veh:

Vehicle

References

  • Al-Shahrour F, Diaz-Uriarte R, Dopazo J (2004) FatiGO: a web tool for finding significant associations of Gene Ontology terms with groups of genes. Bioinformatics 20:578–580

    Article  PubMed  CAS  Google Scholar 

  • Al-Shahrour F, Minguez P, Vaquerizas JM, Conde L, Dopazo J (2005) BABELOMICS: a suit of web tools for functional annotation and analysis of groups of genes in high-throughput experiments. Nucleic Acids Res 33:W460–W464

    Article  PubMed  CAS  Google Scholar 

  • Anderson L, Seilhamer J (1997) A comparison of selected mRNA and protein abundances in human liver. Electrophoresis 18:533–537

    Article  PubMed  CAS  Google Scholar 

  • Barbiero VS, Giambelli R, Musazzi L, Tiraboschi E, Tardito D, Perez J, Drago F, Racagni G, Popoli M (2007) Chronic antidepressants induce redistribution and differential activation of alphaCaM Kinase II between presynaptic compartments. Neuropsychopharmacology advance online publication, 14 March 2007; doi:10.1038/sj.npp.1301378

    Google Scholar 

  • Bonanno G, Giambelli R, Raiteri L, Tiraboschi E, Zappettini S, Musazzi L, Raiteri M, Racagni G, Popoli M (2005) Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J Neurosci 25:3270–3279

    Article  PubMed  CAS  Google Scholar 

  • Boyd-Kimball D, Castegna A, Sultana R, Poon HF, Petroze R, Lynn BC, Klein JB, Butterfield DA (2005) Proteomic identification of proteins oxidized by Abeta(1–42) in synaptosomes: implications for Alzheimer's disease. Brain Res 1044:206–215

    Article  PubMed  CAS  Google Scholar 

  • Caldji C, Francis D, Sharma S, Plotsky PM, Meaney MJ (2000) The effects of early rearing environment on the devepopment of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Neuropsychopharmacology 22:219–229

    Article  PubMed  CAS  Google Scholar 

  • Caspi A, Moffitt TE (2006) Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci 7:583–590

    Article  PubMed  CAS  Google Scholar 

  • Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389

    Article  PubMed  CAS  Google Scholar 

  • Carboni L, Piubelli C, Righetti PG, Jansson B, Domenici E (2002) Proteomic analysis of rat brain tissue: comparison of protocols for two-dimensional gel electrophoresis analysis based on different solubilizing agents. Electrophoresis 23:4132–4141

    Article  PubMed  CAS  Google Scholar 

  • Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4:P3

    Article  PubMed  Google Scholar 

  • Dunkley PR, Jarvie PE, Heath JW, Kidd GJ, Rostas JA (1986) A rapid method for isolation of synaptosomes on Percoll gradients. Brain Res 372:115–129

    Article  PubMed  CAS  Google Scholar 

  • El Khoury A, Gruber SHM, Mϕrk A, Mathé AA (2006) Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression. Prog Neuropsychopharmacol Biol Psychiatr 30:535–540

    Article  CAS  Google Scholar 

  • Fountoulakis M (2004) Application of proteomiics technologies in the investigation of the brain. Mass Spectrom Rev 23:231–258

    Article  PubMed  CAS  Google Scholar 

  • Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatr 49:1023–1039

    Article  CAS  Google Scholar 

  • Henn FA, Edwards E, Anderson D, Vollmayr B (2002) Psychotherapy and antidepressant treatment of depression: evidence for similar neurobiological mechanism. World Psychiatr 1:115–117

    Google Scholar 

  • Hitzemann R (2000) Animal models of psychiatric disorders and their relevance to alcoholism. Alcohol Res Healt 3:149–158

    Google Scholar 

  • Janowsky DS, Risch SC, Parker D, Huey L, Judd L (1980) Increased vulnerability to cholinergic stimulation in affect disorder patients. Psychopharmacol Bull 16:29–31

    PubMed  CAS  Google Scholar 

  • Janowsky DS, Overstreet DH, Nurnberger JI Jr (1994) Is cholinergic sensitivity a genetic marker for the affective disorders? Am J Med Genet 54:335–344

    Article  PubMed  CAS  Google Scholar 

  • Keller MB, Boland RJ (1998) Implications of failing to achieve successful long-term maintenance treatment of recurrent unipolar major depression. Biol Psychiatr 44:348–360

    Article  CAS  Google Scholar 

  • Kramer R, Cohen D (2004) Functional genomics to new drug targets. Nat Rev Drug Discov 3:965–72

    Article  PubMed  CAS  Google Scholar 

  • Ladd CO, Huot RL, Thrivikraman KV, Nemeroff CB, Meaney MJ, Plotsky PM (2000) Long-term behavioural and neuroendocrine adaptations to adverse early experience. Prog Brain Res 122:81–103

    Article  PubMed  CAS  Google Scholar 

  • Lesch KP (2004) Gene-environment interaction and the genetics of depression. J Psychiatr Neurosci 29:174–84

    Google Scholar 

  • Li KW, Hornshaw MP, Van Der Schors RC, Watson R, Tate S, Casetta B, Jimenez CR, Gouwenberg Y, Gundelfinger ED, Smalla KH, Smit AB (2004) Proteomics analysis of rat brain postsynaptic density. Implications of the diverse protein functional groups for the integration of synaptic physiology. J Biol Chem 279:987–1002

    Article  PubMed  CAS  Google Scholar 

  • Liberatori S, Canas B, Tani C, Bini L, Buonocore G, Godovac-Zimmermann J, Mishra OP, Delivoria-Papadopoulos M, Bracci R, Pallini V (2004) Proteomic approach to the identification of voltage-dependent anion channel protein isoforms in guinea pig brain synaptosomes. Proteomics 4:1335–1340

    Article  PubMed  CAS  Google Scholar 

  • Matthews K, Christmas D, Swan J, Sorrel E (2005) Animal models of depression: navigating through the clinical fog. Neurosci Biobehav Rev 29:503–513

    Article  PubMed  Google Scholar 

  • Mello CF, Sultana R, Piroddi M, Cai J, Pierce WM, Klein JB, Butterfield DA (2007) Acrolein induces selective protein carbonylation in synaptosomes. Neuroscience 147:674–679

    Article  PubMed  CAS  Google Scholar 

  • Musazzi L, Ryan B, Barbiero VS, Mallei A, Giambelli R, Tardito D, Gruber SHM, El Khoury A, Andersson W, Anwyl R, Racagni G, Mathé AA, Rowan MJ, Popoli M Early-life stress enhances NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression. Submitted Proc Natl Acad Sci USA 2007

    Google Scholar 

  • Overmier JB, Seligman ME (1967) Effects of inescapable shock upon subsequent escape and avoidance responding. J Comp Physiol Psychol 63:28–33

    Article  PubMed  CAS  Google Scholar 

  • Overstreet DH, Russell RW (1982) Selective breeding for diisopropyl fuorophosphate-sensitivity: behavioural effects of cholinergic agonists and antagonists. Psychopharmacology (Berl.) 78:150–155

    Article  CAS  Google Scholar 

  • Overstreet DH, Friedman E, Mathé AA, Yadid G (2005) The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 29:739–759

    Article  PubMed  CAS  Google Scholar 

  • Paulson L, Martin P, Persson A, Nilsson CL, Ljung E, Westman-Brinkmalm A, Eriksson PS, Blennow K, Davidsson P (2003) Comparative genome- and proteome analysis of cerebral cortex from MK-801-treated rats. J Neurosci Res 71:526–533

    Article  PubMed  CAS  Google Scholar 

  • Plotsky PM, Meaney MJ (1993) Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res Mol Brain Res 18:195–200

    Article  PubMed  CAS  Google Scholar 

  • Pucilowski O, Overstreet DH, Rezvani AH, Janowsky DS (1993) Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression. Physiol Behav 54:1215–1220

    Article  PubMed  CAS  Google Scholar 

  • Raiteri L, Raiteri M (2000) Synaptosomes still viable after 25 years of superfusion. Neurochem Res 25:1265–1274

    Article  PubMed  CAS  Google Scholar 

  • Rohlff C, Hollis K (2003) Modern proteomic strategies in the study of complex neuropsychiatric disorders. Biol Psychiatr 53:847–853

    Article  CAS  Google Scholar 

  • Russel RW, Overstreet DH (1987) Mechanisms underlying sensitivity to organophosphororus anticholinesterase compounds. Prog Neurobiol 28:97–129

    Article  Google Scholar 

  • Stasyk T, Huber LA (2004) Zooming in: fractionation strategies in proteomics. Proteomics 4:3704–3716

    Article  PubMed  CAS  Google Scholar 

  • Satoh K, Takeuchi M, Oda Y, Deguchi-Tawarada M, Sakamoto Y, Matsubara K, Nagasu T, Takai Y (2002) Identification of activity-regulated proteins in the postsynaptic density fraction. Genes Cells 7:187–197

    Article  PubMed  CAS  Google Scholar 

  • Urani A, Chourbaji S, Gass P (2005) Mutant mouse models of depression: candidate genes and current mouse lines. Neurosci Biobehav Rev 29:805–828

    Article  PubMed  CAS  Google Scholar 

  • Vazquez DM, Lopez JF, Van Hoers H, Watson SJ, Levine S (2000) Maternal deprivation regulates serotonin 1A and 2A receptors in the infant rat. Brain Res 855:76–82

    Article  PubMed  CAS  Google Scholar 

  • Vercauteren FG, Bergeron JJ, Vandesande F, Arckens L, Quirion R (2004) Proteomic approaches in brain research and neuropharmacology. Eur J Pharmacol 500:385–398

    Article  PubMed  CAS  Google Scholar 

  • Vollmayr B, Henn FA (2001) Learned helplessness in the rat: improvements in validity and reliability. Brain Res Protoc 8:1–7

    Article  CAS  Google Scholar 

  • Vollmayr B, Henn FA (2003) Stress models of depression. Clin Neurosci Res 3:245–251

    Article  Google Scholar 

  • Vollmayr B, Simonis C, Weber S, Gass P, Henn FA (2003) Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol Psychiatry 54:1035–1040

    Article  PubMed  Google Scholar 

  • Wasinger VC, Cordwell SJ, Cerpa-Poljak A, Yan JX, Gooley AA, Wilkins MR, Duncan MW, Harris R, Williams KL, Humphery-Smith I (1995) Progress with gene-product mapping of the Mollicutes: Mycoplasma genitalium. Electrophoresis 16:1090–1094

    Article  PubMed  CAS  Google Scholar 

  • Willner P (1990) Animal models of depression: an overview. Pharmacol Ther 45:425–455

    Article  PubMed  CAS  Google Scholar 

  • Willner P (1995) Animal models of depression: validity and applications. Adv Biochem Psychopharmacol 49:19–41

    PubMed  CAS  Google Scholar 

  • Wishart TM, Paterson JM, Short DM, Meredith S, Robertson KA, Sutherland C, Cousin MA, Dutia MB, Gillingwater TH (2007) Differential proteomic analysis of synaptic proteins identifies potential cellular targets and protein mediators of synaptic neuroprotection conferred by the slow Wallerian degeneration (Wld) gene. Mol Cell Proteomics 8:1318–1330

    Article  Google Scholar 

  • Witzmann FA, Arnold RJ, Bai F, Hrncirova P, Kimpel MW, Mechref YS, McBride WJ, Novotny MV, Pedrick NM, Ringham HN, Simon JR (2005) A proteomic survey of rat cerebral cortical synaptosomes. Proteomics 5:2177–2201

    Article  PubMed  CAS  Google Scholar 

  • Yadid G, Nakash R, Deri I, Tamar G, Kinor N, Gispan I, Zangen A (2000) Elucidation of the neurobiology of depression: insights from a novel genetic animal model. Prog Neurobiol 62:353–378

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was funded by a European Union (6th Framework Program) grant for project GENDEP (contract no. LSHB-CT-2003-503428) and by the Swedish Medical Research Council grant 10414 (to AAM).

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Correspondence to Maurizio Popoli .

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Mallei, A. et al. (2008). Synaptoproteomics of Existing and new Animal Models of Depression. In: Turck, C. (eds) Biomarkers for Psychiatric Disorders. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-79251-4_8

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