Abstract
A genomic region neighboring the α-synuclein gene, on rat chromosome 4, has been associated with anxiety- and alcohol-related behaviors in different rat strains. In this study, we have investigated potential molecular and physiological links between α-synuclein and the behavioral differences observed between Lewis (LEW) and Spontaneously Hypertensive (SHR) inbred rats, a genetic model of anxiety. As expected, LEW rats appeared more fearful than SHR rats in three anxiety models: open field, elevated plus maze and light/dark box. Moreover, LEW rats displayed a higher preference for alcohol and consumed higher quantities of alcohol than SHR rats. α-Synuclein mRNA and protein concentrations were higher in the hippocampus, but not the hypothalamus of LEW rats. This result inversely correlated with differences in dopamine turnover in the hippocampus of LEW and SHR rats, supporting the hypothesis that α-synuclein is important in the downregulation of dopamine neurotransmission. A novel single nucleotide polymorphism was identified in the 3′-untranslated region (3′-UTR) of the α-synuclein cDNA between these two rat strains. Plasmid constructs based on the LEW 3′-UTR sequence displayed increased expression of a reporter gene in transiently transfected PC12 cells, in accordance with in-vivo findings, suggesting that this nucleotide exchange might participate in the differential expression of α-synuclein between LEW and SHR rats. These results are consistent with a novel role for α-synuclein in modulating rat anxiety-like behaviors, possibly through dopaminergic mechanisms. Since the behavioral and genetic differences between these two strains are the product of independent evolutionary histories, the possibility that polymorphisms in the α-synuclein gene may be associated with vulnerability to anxiety-related disorders in humans requires further investigation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Anagnostaras SG, Craske MG, Fanselow MS . Anxiety: at the intersection of genes and experience. Nat Neurosci 1999; 2: 780–782.
WHO-World Mental Health Survey Consortium. Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. JAMA 2004; 2: 2581–2590.
Brodkin ES, Nestler EJ . Quantitative trait locus analysis: a new tool for psychiatric genetics. Neuroscientist 1998; 4: 317–323.
Ramos A, Mormède P . Stress and emotionality: a multidimensional and genetic approach. Neurosci Biobehav Rev 1998; 22: 33–57.
Henninger MSH, Ohl F, Hölter SM, Weinßenbacher P, Toschi N, Lörscher P et al. Unconditioned anxiety and social behaviour in two rat lines selectively bred for high and low anxiety-related behaviour. Behav Brain Res 2000; 111: 153–163.
Toye AA, Cox R . Behavioral genetics: anxiety under interrogation. Curr Biol 2001; 11: 473–476.
Turri MG, Datta SR, Defries J, Henderson ND, Flint J . QTL analysis identifies multiple behavioral dimensions in ethological tests of anxiety in laboratory mice. Curr Biol 2001; 11: 725–734.
Wood SJ, Toth M . Molecular pathways of anxiety revealed by knockout mice. Mol Neurobiol 2001; 23: 101–119.
Clément Y, Calatayud F, Belzung C . Genetic basis of anxiety-like behaviour: a critical review. Brain Res Bull 2002; 57: 57–71.
Flint J, Corley R, De Fries JC, Fulker DW, Gray JA, Miller S et al. A simple genetic basis for a complex psychological trait in laboratory mice. Science 1995; 269: 1432–1435.
Flint J . Analysis of quantitative trait loci that influence animal behavior. J Neurobiol 2003; 54: 46–77.
Ramos A, Berton O, Mormède P, Chaouloff F . A multiple-test study of anxiety-related behaviours in six inbred rat strains. Behav Brain Res 1997; 85: 57–69.
Ramos A, Mellerin Y, Mormède P, Chaouloff F . A genetic and multifactorial analysis of anxiety-related behaviours in Lewis and SHR intercrosses. Behav Brain Res 1998; 96: 195–205.
Ramos A, Moisan MP, Chaouloff F, Mormède C, Mormède F . Identification of female-specific QTLs affecting an emotionality-related behavior in rats. Mol Psychiatry 1999; 4: 453–462.
Gentsch C, Lichtsteiner M, Feer H . Open field and elevated plus-maze: a behavioural comparison between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats and the effects of chlordiazepoxide. Behav Brain Res 1987; 25: 101–107.
Treit D, Fundytus M . Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol Biochem Behav 1989; 31: 959–962.
Simon P, Dupuis R, Costentin J . Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res 1994; 61: 59–64.
Nazar M, Jessa M, Plaznik A . Benzodiazepine-GABAa receptor complex ligands in two models of anxiety. J Neural Transm 1997; 104: 733–746.
Mormède P, Moneva E, Bruneval C, Chaouloff F, Moisan MP . Marker-assisted selection of a neuro-behavioural trait related to behavioural inhibition in the SHR strain, an animal model of ADHD. Genes Brain Behav 2002; 1: 111–116.
Vendruscolo LF, Terenina-Rigaldie E, Raba F, Ramos A, Takahashi RN, Mormede P . Evidence for a female-specific effect of a chromosome 4 locus on anxiety-related behaviors and ethanol drinking in rats. Genes Brain Behav 2006; 5: 441–450.
Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K . Immunohistochemical comparison of alpha- and beta-synuclein in adult rat central nervous system. Brain Res 2002; 941: 118–126.
Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ . A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 2002; 22: 3090–3099.
Peng XM, Tehranian R, Dietrich P, Stefanis L, Perez RG . α-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. J Cell Sci 2005; 118: 3523–3530.
Kaplan B, Ratner V, Haas E . Alpha-synuclein: its biological function and role in neurodegenerative diseases. J Mol Neurosci 2003; 20: 83–92.
Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M . Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett 1998; 251: 205–208.
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M . alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci USA 1998; 95: 6469–6473.
Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VMY et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol 1998; 152: 879–884.
Trojanowski JQ, Lee VMY . Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for the pathogenesis of Parkinson disease and Lewy body dementia. Arch Neurol 1998; 55: 151–152.
Bönsch D, Reulbach U, Bayerlein K, Hillemacher T, Kornhuber J, Bleich S . Elevated alpha synuclein mRNA levels are associated with craving in patients with alcoholism. Biol Psychiatry 2004; 56: 984–986.
Bönsch D, Greifenberg V, Bayerlein K, Biermann T, Reulbach U, Hillemacher T et al. Alpha-synuclein protein levels are increased in alcoholic patients and are linked to craving. Alcohol Clin Exp Res 2005; 29: 763–765.
Liang T, Spence J, Liu L, Strother WN, Chang HW, Ellison JA et al. α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats. Proc Natl Acad Sci USA 2003; 100: 4690–4695.
Richard IH . Anxiety disorders in Parkinson's disease. Adv Neurol 2005; 96: 42–55.
Morris EP, Stewart SH, Ham LS . The relationship between social anxiety disorder and alcohol use disorders: a critical review. Clin Psychol Rev 2005; 25: 734–760.
Terra MB, Barros HM, Stein AT, Figueira I, Jorge MR, Palermo LH et al. Social anxiety disorder in 300 patients hospitalized for alcoholism in Brazil: high prevalence and undertreatment. Compr Psychiatry 2006; 47: 463–467.
Spanagel R, Montkowski A, Allingham K, Stöhr T, Shoaib M, Holsboer F et al. Anxiety: a potential predictor of vulnerability to the initiation of ethanol self-administration in rats. Psychopharmacology (Berl) 1995; 122: 369–373.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al. Accurate normalization of real-time quantitative RT–PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002; 3: 1–12.
van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S et al. Neuropathology in mice expressing human alpha-synuclein. J Neurosci 2000; 20: 6021–6029.
Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT . The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 2002; 111: 209–218.
Bradford MM . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248–254.
Graham FL, van der Eb AJ . Transformation of rat cells by DNA of human adenovirus 5. Virology 1973; 54: 536–539.
Ramos A, Kangerski AL, Basso PF, Da Silva Santos JE, Assreuy J, Vendruscolo LF et al. Evaluation of Lewis and SHR rat strains as a genetic model for the study of anxiety and pain. Behav Brain Res 2002; 129: 113–123.
Izídio GS, Lopes DM, Spricigo Jr L, Ramos A . Common variations in the pretest environment influence genotypic comparisons in models of anxiety. Genes Brain Behav 2005; 4: 412–419.
Dawson DA, Grant BF, Ruan WJ . The association between stress and drinking: modifying effects of gender and vulnerability. Alcohol Alcohol 2005; 40: 453–460.
Ducci F, Enoch MA, Funt S, Virkkunen M, Albaugh B, Goldman D . Increased anxiety and other similarities in temperament of alcoholics with and without antisocial personality disorder across three diverse populations. Alcohol 2007; 41: 3–12.
Conger JJ . Alcoholism: theory, problem and challenge. II. Reinforcement theory and the dynamics of alcoholism. Q J Stud Alcohol 1956; 17: 296–305.
Greeley J, Oei T . Alcohol and tension reduction. In: Leonard KE, Blane HT (eds). Psychological Theories of Drinking and Alcoholism. Guilford Press: New York, 1999, pp 14–53.
Pandey SC, Zhang H, Roy A, Xu T . Deficits in amygdaloid camp-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J Clin Invest 2005; 115: 2762–2773.
Da Silva GE, Ramos A, Takahashi RN . Comparison of voluntary ethanol intake by two pairs of rat lines used as genetic models of anxiety. Braz J Med Biol Res 2004; 37: 1511–1517.
Bice P, Foroud T, Bo R, Castelluccio P, Lumeng L, Li TK et al. Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines. Mamm Genome 1998; 9: 949–955.
Carr LG, Foroud T, Bice P, Gobbett T, Ivashina J, Edenberg H et al. A quantitative trait locus for alcohol consumption in selectively bred rat lines. Alcohol Clin Exp Res 1998; 22: 884–887.
Terenina-Rigaldie E, Jones BC, Mormède P . Pleiotropic effect of a locus on chromosome 4 influencing alcohol drinking and emotional reactivity in rats. Genes Brain Behav 2003; 2: 125–131.
Terenina-Rigaldie E, Moisan M-P, Colas A, Beaugé F, Shah KV, Jones BC et al. Genetics of behaviour: phenotypic and molecular study of rats derived from high- and low-alcohol consuming lines. Pharmacogenetics 2003; 13: 543–554.
Stewart RB, Gatto GJ, Lumeng L, Li T-K, Murphy JM . Comparison of alcohol-preferring (P) and nonpreferring (NP) rats on tests of anxiety and for the anxiolytic effects of ethanol. Alcohol 1993; 10: 1–10.
Maroteaux L, Scheller RH . The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Brain Res Mol Brain Res 1991; 11: 335–343.
Petersen K, Olesen OF, Mikkelsen JD . Developmental expression of alpha-synuclein in rat hippocampus and cerebral cortex. Neuroscience 1999; 91: 651–659.
Andringa G, Du F, Chase TN, Bennett MC . Mapping of rat brain using the synuclein-1 monoclonal antibody reveals somatodendritic expression of alpha-synuclein in populations of neurons homologous to those vulnerable to Lewy body formation in human synucleopathies. J Neuropathol Exp Neurol 2003; 62: 1060–1075.
Adamczyk A, Solecka J, Strosznajder JB . Expression of alpha-synuclein in different brain parts of adult and aged rats. J Physiol Pharmacol 2005; 56: 29–37.
Malatynska E, Pinhasov A, Crooke J, Horowitz D, Brenneman DE, Ilyin SE . Levels of mRNA coding for alpha-, beta-, and gamma-synuclein in the brains of newborn, juvenile, and adult rats. J Mol Neurosci 2006; 29: 269–277.
Gray JA, McNaughton N . The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-hippocampal System. Oxford University Press: Oxford, 2000.
Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T et al. Regional dissociations within the hippocampus—memory and anxiety. Neurosci Biobehav Rev 2004; 28: 273–283.
Kalisch R, Schubert M, Jacob W, Kessler MS, Hemauer R, Wigger A et al. Anxiety and hippocampus volume in the rat. Neuropsychopharmacology 2006; 31: 925–932.
Nascimento Häckl LP, Carobrez AP . Distinct ventral and dorsal hippocampus AP5 anxiolytic effects revealed in the elevated plus-maze task in rats. Neurobiol Learn Mem 2007; 88: 177–185.
Lee VM, Trojanowski JQ . Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 2006; 5: 33–38.
Farrer M, Maraganore DM, Lockhart P, Singleton A, Lesnick TG, de Andrade M et al. alpha-Synuclein gene haplotypes are associated with Parkinson's disease. Hum Mol Genet 2001; 10: 1847–1851.
Mueller JC, Fuchs J, Hofer A, Zimprich A, Lichtner P, Illig T et al. Multiple regions of alpha-synuclein are associated with Parkinson's disease. Ann Neurol 2005; 57: 535–541.
Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Krüger R et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006; 296: 661–670.
Mizuta I, Satake W, Nakabayashi Y, Ito C, Suzuki S, Momose Y et al. Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease. Hum Mol Genet 2006; 15: 1151–1158.
Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J et al. Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Ann Neurol 2007; 62: 145–153.
Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho W-H, Castillo PE et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 2000; 25: 239–252.
Masliah E, Rockstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000; 287: 1265–1269.
Lotharius J, Barg S, Wiekop P, Lundberg C, Raymon HK, Brundin P . Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J Biol Chem 2002; 11: 38884–38894.
Liang T, Carr LG . Regulation of alpha-synuclein expression in alcohol-preferring and -non preferring rats. J Neurochem 2006; 99: 470–482.
Cappell H, Herman CP . Alcohol and tension reduction. A review. Q J Stud Alcohol 1972; 33: 33–64.
Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990; 264: 2511–2518.
Schuckit MA, Hesselbrock V . Alcohol dependence and anxiety disorders: what is the relationship? Am J Psychiatry 1994; 151: 1723–1734.
Schuckit MA, Hesselbrock VM, Tipp J, Nurnberger Jr JI, Authenelli RM, Crowey RR . The prevalence of major anxiety disorders in relatives of alcohol dependent men and women. J Stud Alcohol 1995; 56: 309–317.
Cornelius JR, Bukstein O, Salloum I, Clark D . Alcohol and psychiatric comorbidity. Recent Dev Alcohol 2003; 16: 361–374.
Caldarone B, Saavedra C, Tartaglia K, Wehner JM, Dudek BC, Flaherty L . Quantitative trait loci analysis affecting contextual conditioning in mice. Nat Genet 1997; 17: 335–337.
Wehner JM, Radcliffe RA, Rosmann ST, Christensen SC, Rasmussen DL, Fulker DW et al. Quantitative trait locus analysis of contextual fear conditioning in mice. Nat Genet 1997; 17: 331–334.
Kovács P, Voigt B, Klöting I . Alleles of the spontaneously hypertensive rat decrease blood pressure at loci on chromosomes 4 and 13. Biochem Biophys Res Commun 1997; 238: 586–589.
Llamas B, Contesse V, Guyonnet-Duperat V, Vaudry H, Mormède P, Moisan MP . QTL mapping for traits associated with stress neuroendocrine reactivity in rats. Mamm Genome 2005; 16: 505–515.
Silva GJ, Pereira AC, Krieger EM, Krieger JE . Genetic mapping of a new heart rate QTL on chromosome 8 of spontaneously hypertensive rats. BMC Med Genet 2007; 8: 17.
Acknowledgements
We thank Dr José Eduardo Krieger for laboratory facilities, Dr Hiro Goto for the vivarium, Dr Vilma R Martins for supplying the PC12 cells and Dr Randy J Nelson for the first editorial assistance. This study was supported by grants from the Sao Paulo State Foundation for Research Support (FAPESP: 05/02020-2 and 06/06904-5), from Studies and Projects Financier (FINEP: 0104/0258/00) and the Pronex 427/2003 project from Fapesc/CNPq. S Chiavegatto and A Ramos are research scholars from CNPq; GS Izídio had a scholarship from CNPq.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chiavegatto, S., Izidio, G., Mendes-Lana, A. et al. Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety. Mol Psychiatry 14, 894–905 (2009). https://doi.org/10.1038/mp.2008.43
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2008.43
Keywords
This article is cited by
-
Genetic effects in a progressive model of parkinsonism induced by reserpine
Psychopharmacology (2023)
-
Generalized and social anxiety disorder interactomes show distinctive overlaps with striosome and matrix interactomes
Scientific Reports (2021)
-
Neuroendocrine disruption by bisphenol A and/or di(2-ethylhexyl) phthalate after prenatal, early postnatal and lactational exposure
Environmental Science and Pollution Research (2021)
-
The Quinpirole Hypolocomotive Effects are Strain and Route of Administration Dependent in SHR and SLA16 Isogenic Rats
Behavior Genetics (2017)
-
The influence of sex and estrous cycle on QTL for emotionality and ethanol consumption
Mammalian Genome (2011)