期刊论文详细信息
BMC Neuroscience
The influence of serotonin transporter polymorphisms on cortical activity: A resting EEG study
Tai-Jui Chen4  Hung-Chi Wu3  Shih-Jen Tsai5  Chen-Jee Hong5  Younger WY Yu1  Tien-Wen Lee2 
[1] Yu's Psychiatric Clinic, Kaohsiung, Taiwan;College of Medicine, Chang Gung University, Taoyuan County, Taiwan;Kai-Suan Psychiatric Hospital, Kaohsiung, Taiwan;Department of Occupational Therapy, I-Shou University, Kaohsiung County, Taiwan;School of Medicine, National Yang-Ming University, Taipei, Taiwan
关键词: polymorphism;    5-HTTVNTR;    5-HTTLPR;    power spectrum;    electroencephalography (EEG);   
Others  :  1174815
DOI  :  10.1186/1471-2202-12-33
 received in 2010-10-18, accepted in 2011-04-20,  发布年份 2011
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【 摘 要 】

Background

The serotonin transporter gene (5-HTT) is a key regulator of serotonergic neurotransmission and has been linked to various psychiatric disorders. Among the genetic variants, polymorphisms in the 5-HTT gene-linked polymorphic region (5-HTTLPR) and variable-number-of-tandem-repeat in the second intron (5-HTTVNTR) have functional consequences. However, their genetic impact on cortical oscillation remains unclear. This study examined the modulatory effects of 5-HTTLPR (L-allele carriers vs. non-carriers) and 5-HTTVNTR (10-repeat allele carriers vs. non-carriers) polymorphism on regional neural activity in a young female population.

Methods

Blood samples and resting state eyes-closed electroencephalography (EEG) signals were collected from 195 healthy women and stratified into 2 sets of comparisons of 2 groups each: L-allele carriers (N = 91) vs. non-carriers for 5-HTTLPR and 10-repeat allele carriers (N = 25) vs. non-carriers for 5-HTTVNTR. The mean power of 18 electrodes across theta, alpha, beta, gamma, gamma1, and gamma2 frequencies was analyzed. Between-group statistics were performed by an independent t-test, and global trends of regional power were quantified by non-parametric analyses.

Results

Among 5-HTTVNTR genotypes, 10-repeat allele carriers showed significantly low regional power at gamma frequencies across the brain. We noticed a consistent global trend that carriers with low transcription efficiency of 5-HTT possessed low regional powers, regardless of frequency bands. The non-parametric analyses confirmed this observation, with P values of 3.071 × 10-8 and 1.459 × 10-12 for 5-HTTLPR and 5-HTTVNTR, respectively.

Conclusions and Limitations

Our analyses showed that genotypes with low 5-HTT activity are associated with less local neural synchronization during relaxation. The implication with respect to genetic vulnerability of 5-HTT across a broad range of psychiatric disorders is discussed. Given the low frequency of 10-repeat allele of 5-HTTVNTR in our research sample, the possibility of false positive findings should also be considered.

【 授权许可】

   
2011 Lee et al; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]Hoehe MR, Wendel B, Grunewald I, Chiaroni P, Levy N, Morris-Rosendahl D, Macher JP, Sander T, Crocq MA: Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders. Am J Med Genet 1998, 81:1-3.
  • [2]Kuzelova H, Ptacek R, Macek M: The serotonin transporter gene (5-HTT) variant and psychiatric disorders: review of current literature. Neuro Endocrinol Lett 2010, 31:4-10.
  • [3]Gorwood P, Batel P, Ades J, Hamon M, Boni C: Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior. Biol Psychiatry 2000, 48:259-264.
  • [4]Ramasubbu R, Tobias R, Bech-Hansen NT: Extended evaluation of serotonin transporter gene functional polymorphisms in subjects with post-stroke depression. Can J Psychiatry 2008, 53:197-201.
  • [5]Barton DA, Esler MD, Dawood T, Lambert EA, Haikerwal D, Brenchley C, Socratous F, Hastings J, Guo L, Wiesner G, et al.: Elevated brain serotonin turnover in patients with depression: effect of genotype and therapy. Arch Gen Psychiatry 2008, 65:38-46.
  • [6]Lau JY, Goldman D, Buzas B, Fromm SJ, Guyer AE, Hodgkinson C, Monk CS, Nelson EE, Shen PH, Pine DS, Ernst M: Amygdala function and 5-HTT gene variants in adolescent anxiety and major depressive disorder. Biol Psychiatry 2009, 65:349-355.
  • [7]You JS, Hu SY, Chen B, Zhang HG: Serotonin transporter and tryptophan hydroxylase gene polymorphisms in Chinese patients with generalized anxiety disorder. Psychiatr Genet 2005, 15:7-11.
  • [8]Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM, Smith CA: Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 1996, 347:731-733.
  • [9]Nellissery M, Feinn RS, Covault J, Gelernter J, Anton RF, Pettinati H, Moak D, Mueller T, Kranzler HR: Alleles of a functional serotonin transporter promoter polymorphism are associated with major depression in alcoholics. Alcohol Clin Exp Res 2003, 27:1402-1408.
  • [10]Ohara K, Suzuki Y, Ochiai M, Tsukamoto T, Tani K, Ohara K: A variable-number-tandem-repeat of the serotonin transporter gene and anxiety disorders. Prog Neuropsychopharmacol Biol Psychiatry 1999, 23:55-65.
  • [11]Tsai SJ, Ouyang WC, Hong CJ: Association for serotonin transporter gene variable number tandem repeat polymorphism and schizophrenic disorders. Neuropsychobiology 2002, 45:131-133.
  • [12]Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996, 274:1527-1531.
  • [13]Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, Davis S, Kirshner MA, Houck PR, Stack JA, et al.: Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000, 23:587-590.
  • [14]Hu XZ, Rush AJ, Charney D, Wilson AF, Sorant AJ, Papanicolaou GJ, Fava M, Trivedi MH, Wisniewski SR, Laje G, et al.: Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry 2007, 64:783-792.
  • [15]Murphy GM Jr, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF: Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 2004, 61:1163-1169.
  • [16]Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP: Allelic variation of human serotonin transporter gene expression. J Neurochem 1996, 66:2621-2624.
  • [17]Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA: An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 2005, 29:8-16.
  • [18]Dannlowski U, Ohrmann P, Bauer J, Deckert J, Hohoff C, Kugel H, Arolt V, Heindel W, Kersting A, Baune BT, Suslow T: 5-HTTLPR biases amygdala activity in response to masked facial expressions in major depression. Neuropsychopharmacology 2008, 33:418-424.
  • [19]Dannlowski U, Konrad C, Kugel H, Zwitserlood P, Domschke K, Schoning S, Ohrmann P, Bauer J, Pyka M, Hohoff C, et al.: Emotion specific modulation of automatic amygdala responses by 5-HTTLPR genotype. Neuroimage 2009.
  • [20]Rao H, Gillihan SJ, Wang J, Korczykowski M, Sankoorikal GM, Kaercher KA, Brodkin ES, Detre JA, Farah MJ: Genetic variation in serotonin transporter alters resting brain function in healthy individuals. Biol Psychiatry 2007, 62:600-606.
  • [21]Graff-Guerrero A, De la Fuente-Sandoval C, Camarena B, Gomez-Martin D, Apiquian R, Fresan A, Aguilar A, Mendez-Nunez JC, Escalona-Huerta C, Drucker-Colin R, Nicolini H: Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism. Neuroimage 2005, 25:1197-1204.
  • [22]Bertolino A, Arciero G, Rubino V, Latorre V, De Candia M, Mazzola V, Blasi G, Caforio G, Hariri A, Kolachana B, et al.: Variation of human amygdala response during threatening stimuli as a function of 5'HTTLPR genotype and personality style. Biol Psychiatry 2005, 57:1517-1525.
  • [23]Tsai SJ, Hong CJ, Cheng CY: Serotonin transporter genetic polymorphisms and harm avoidance in the Chinese. Psychiatr Genet 2002, 12:165-168.
  • [24]Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A: Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 1997, 6:2233-2238.
  • [25]Brune CW, Kim SJ, Salt J, Leventhal BL, Lord C, Cook EH Jr: 5-HTTLPR Genotype-Specific Phenotype in Children and Adolescents With Autism. Am J Psychiatry 2006, 163:2148-2156.
  • [26]Hranilovic D, Stefulj J, Furac I, Kubat M, Balija M, Jernej B: Serotonin transporter gene promoter (5-HTTLPR) and intron 2 (VNTR) polymorphisms in Croatian suicide victims. Biol Psychiatry 2003, 54:884-889.
  • [27]Frei E, Gamma A, Pascual-Marqui R, Lehmann D, Hell D, Vollenweider FX: Localization of MDMA-induced brain activity in healthy volunteers using low resolution brain electromagnetic tomography (LORETA). Hum Brain Mapp 2001, 14:152-165.
  • [28]Saletu B, Grunberger J, Anderer P, Linzmayer L, Zyhlarz G: Comparative pharmacodynamic studies with the novel serotonin uptake-enhancing tianeptine and -inhibiting fluvoxamine utilizing EEG mapping and psychometry. J Neural Transm 1996, 103:191-216.
  • [29]Knott VJ, Howson AL, Perugini M, Ravindran AV, Young SN: The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects. Biol Psychiatry 1999, 46:229-238.
  • [30]Schenk GK, Filler W, Ranft W, Zerbin D: Double-blind comparisons of a selective serotonin reuptake inhibitor, zimelidine, and placebo on quantified EEG parameters and psychological variables. Acta Psychiatr Scand Suppl 1981, 290:303-313.
  • [31]Siepmann M, Grossmann J, Muck-Weymann M, Kirch W: Effects of sertraline on autonomic and cognitive functions in healthy volunteers. Psychopharmacology (Berl) 2003, 168:293-298.
  • [32]Siepmann T, Mueck-Weymann M, Oertel R, Kirch W, Pittrow D, Siepmann M: The effects of venlafaxine on cognitive functions and quantitative EEG in healthy volunteers. Pharmacopsychiatry 2008, 41:146-150.
  • [33]Ahveninen J, Jaaskelainen IP, Pennanen S, Liesivuori J, Ilmoniemi RJ, Kahkonen S: Auditory selective attention modulated by tryptophan depletion in humans. Neurosci Lett 2003, 340:181-184.
  • [34]Kahkonen S, Jaaskelainen IP, Pennanen S, Liesivuori J, Ahveninen J: Acute tryptophan depletion decreases intensity dependence of auditory evoked magnetic N1/P2 dipole source activity. Psychopharmacology (Berl) 2002, 164:221-227.
  • [35]Ahveninen J, Kahkonen S, Pennanen S, Liesivuori J, Ilmoniemi RJ, Jaaskelainen IP: Tryptophan depletion effects on EEG and MEG responses suggest serotonergic modulation of auditory involuntary attention in humans. Neuroimage 2002, 16:1052-1061.
  • [36]Young AH, Hughes JH, Marsh VR, Ashton CH: Acute tryptophan depletion attenuates auditory event related potentials in bipolar disorder: a preliminary study. J Affect Disord 2002, 69:83-92.
  • [37]Kahkonen S, Ahveninen J, Jaaskelainen IP, Pennanen S, Liesivuori J, Nikulin VV: Acute tryptophan depletion does not change somatosensory evoked magnetic fields. Psychopharmacology (Berl) 2003, 170:332-333.
  • [38]McAllister-Williams RH, Massey AE, Rugg MD: Effects of tryptophan depletion on brain potential correlates of episodic memory retrieval. Psychopharmacology (Berl) 2002, 160:434-442.
  • [39]Hughes JH, Ashton CH, Matthews D, Young AH: Acute depletion of plasma tryptophan does not alter electrophysiological variables in healthy males. Psychopharmacology (Berl) 2000, 152:119-121.
  • [40]Bismark AW, Moreno FA, Stewart JL, Towers DN, Coan JA, Oas J, Erickson RP, Allen JJ: Polymorphisms of the HTR1a allele are linked to frontal brain electrical asymmetry. Biol Psychol 2010, 83:153-158.
  • [41]Enge S, Fleischhauer M, Lesch KP, Strobel A: On the role of serotonin and effort in voluntary attention: Evidence of genetic variation in N1 modulation. Behav Brain Res 2010.
  • [42]Sysoeva OV, Maluchenko NV, Smirnov KS, Shleptsova VA, Ivanitsky AM, Tonevitsky AG: Peculiarities of brain information processing in persons with different serotonin transporter gene variants. Bull Exp Biol Med 2009, 148:731-734.
  • [43]Mulert C, Juckel G, Brunnmeier M, Karch S, Leicht G, Mergl R, Moller HJ, Hegerl U, Pogarell O: Prediction of treatment response in major depression: integration of concepts. J Affect Disord 2007, 98:215-225.
  • [44]Jelic V, Kowalski J: Evidence-based evaluation of diagnostic accuracy of resting EEG in dementia and mild cognitive impairment. Clin EEG Neurosci 2009, 40:129-142.
  • [45]Neuper C, Grabner RH, Fink A, Neubauer AC: Long-term stability and consistency of EEG event-related (de-)synchronization across different cognitive tasks. Clin Neurophysiol 2005, 116:1681-1694.
  • [46]Hermens DF, Soei EX, Clarke SD, Kohn MR, Gordon E, Williams LM: Resting EEG theta activity predicts cognitive performance in attention-deficit hyperactivity disorder. Pediatr Neurol 2005, 32:248-256.
  • [47]Hoptman MJ, Davidson RJ: Baseline EEG asymmetries and performance on neuropsychological tasks. Neuropsychologia 1998, 36:1343-1353.
  • [48]Coben LA, Chi D, Snyder AZ, Storandt M: Replication of a study of frequency analysis of the resting awake EEG in mild probable Alzheimer's disease. Electroencephalogr Clin Neurophysiol 1990, 75:148-154.
  • [49]Maluchenko NV, Schegolkova JV, Kulikova MA, Timofeeva MA, Shlepcova VA, Sysoeva OV, Tonevitsky AG: Gender effects on association of serotonin transporter gene polymorphism with symptoms of central fatigue. Bull Exp Biol Med 2009, 147:462-465.
  • [50]Mizuno T, Aoki M, Shimada Y, Inoue M, Nakaya K, Takahashi T, Itoyama Y, Kanazawa M, Utsumi A, Endo Y, et al.: Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety. J Psychosom Res 2006, 60:91-97.
  • [51]Du L, Bakish D, Hrdina PD: Gender differences in association between serotonin transporter gene polymorphism and personality traits. Psychiatr Genet 2000, 10:159-164.
  • [52]Duffy FH, Lyer G, Surwillo WW: Clinical electroencephalography and topographical brain mapping. New York: Springer-Verlag; 1989.
  • [53]Schneider S, Roessli D, Excoffier L: Arlequin ver 2.000: A software for population genetics data analysis. Genetics and Biometry Laboratory, University of Geneva, Switzerland; 2000.
  • [54]van Belle G: Statistical Rules of Thumb. 1st edition. New York: Wiley-Interscience; 2002.
  • [55]Kishida I, Aklillu E, Kawanishi C, Bertilsson L, Agren H: Monoamine metabolites level in CSF is related to the 5-HTT gene polymorphism in treatment-resistant depression. Neuropsychopharmacology 2007, 32:2143-2151.
  • [56]Haydon PG, McCobb DP, Kater SB: Serotonin selectively inhibits growth cone motility and synaptogenesis of specific identified neurons. Science 1984, 226:561-564.
  • [57]Whitaker-Azmitia PM, Azmitia EC: Stimulation of astroglial serotonin receptors produces culture media which regulates growth of serotonergic neurons. Brain Res 1989, 497:80-85.
  • [58]Buznikov GA, Shmukler YB, Lauder JM: From oocyte to neuron: do neurotransmitters function in the same way throughout development? Cell Mol Neurobiol 1996, 16:537-559.
  • [59]Chubakov AR, Gromova EA, Konovalov GV, Chumasov EI, Sarkisova EF: Effect of serotonin on the development of a rat cerebral cortex tissue culture. Neurosci Behav Physiol 1986, 16:490-497.
  • [60]Djavadian RL: Serotonin and neurogenesis in the hippocampal dentate gyrus of adult mammals. Acta Neurobiol Exp (Wars) 2004, 64:189-200.
  • [61]Jacobs BL: Adult brain neurogenesis and depression. Brain Behav Immun 2002, 16:602-609.
  • [62]Gould E: Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 1999, 21:46S-51S.
  • [63]Cavallini MC, Di Bella D, Siliprandi F, Malchiodi F, Bellodi L: Exploratory factor analysis of obsessive-compulsive patients and association with 5-HTTLPR polymorphism. Am J Med Genet 2002, 114:347-353.
  • [64]Golimbet VE, Lebedeva IS, Alfimova MV, Korovaitseva GI, Lezheiko TV, Abramova LI, Kaleda VG: [Acoustic evoked potentials, serotonin transporter gene polymorphism and some psychopathological and psychological features in patients with schizophrenia and their relatives]. Zh Nevrol Psikhiatr Im S S Korsakova 2006, 106:44-49.
  • [65]Strobel A, Debener S, Schmidt D, Hunnerkopf R, Lesch KP, Brocke B: Allelic variation in serotonin transporter function associated with the intensity dependence of the auditory evoked potential. Am J Med Genet B Neuropsychiatr Genet 2003, 118B:41-47.
  • [66]Hegerl U, Gallinat J, Juckel G: Event-related potentials. Do they reflect central serotonergic neurotransmission and do they predict clinical response to serotonin agonists? J Affect Disord 2001, 62:93-100.
  • [67]Hegerl U, Juckel G: Identifying psychiatric patients with serotonergic dysfunctions by event-related potentials. World J Biol Psychiatry 2000, 1:112-118.
  • [68]Asberg M: Neurotransmitters and suicidal behavior. The evidence from cerebrospinal fluid studies. Ann N Y Acad Sci 1997, 836:158-181.
  • [69]Lin PY, Tsai G: Association between serotonin transporter gene promoter polymorphism and suicide: results of a meta-analysis. Biol Psychiatry 2004, 55:1023-1030.
  • [70]Knyazev GG, Savostyanov AN, Levin EA: Uncertainty, anxiety, and brain oscillations. Neurosci Lett 2005, 387:121-125.
  • [71]Sviderskaia NE, Prudnikov VN, Antonov AG: Characteristics of EEG signs of anxiety in human. Zh Vyssh Nerv Deiat Im I P Pavlova 2001, 51:158-165.
  • [72]Oathes DJ, Ray WJ, Yamasaki AS, Borkovec TD, Castonguay LG, Newman MG, Nitschke J: Worry, generalized anxiety disorder, and emotion: evidence from the EEG gamma band. Biol Psychol 2008, 79:165-170.
  • [73]Barry RJ, Rushby JA, Wallace MJ, Clarke AR, Johnstone SJ, Zlojutro I: Caffeine effects on resting-state arousal. Clin Neurophysiol 2005, 116:2693-2700.
  • [74]Bonnet MH, Arand DL: Impact of activity and arousal upon spectral EEG parameters. Physiol Behav 2001, 74:291-298.
  • [75]Frodl T, Reinhold E, Koutsouleris N, Donohoe G, Bondy B, Reiser M, Moller HJ, Meisenzahl EM: Childhood stress, serotonin transporter gene and brain structures in major depression. Neuropsychopharmacology 2010, 35:1383-1390.
  • [76]Pacheco J, Beevers CG, Benavides C, McGeary J, Stice E, Schnyer DM: Frontal-limbic white matter pathway associations with the serotonin transporter gene promoter region (5-HTTLPR) polymorphism. J Neurosci 2009, 29:6229-6233.
  • [77]Hickie IB, Naismith SL, Ward PB, Scott EM, Mitchell PB, Schofield PR, Scimone A, Wilhelm K, Parker G: Serotonin transporter gene status predicts caudate nucleus but not amygdala or hippocampal volumes in older persons with major depression. J Affect Disord 2007, 98:137-142.
  • [78]Summerfield C, Jack AI, Burgess AP: Induced gamma activity is associated with conscious awareness of pattern masked nouns. Int J Psychophysiol 2002, 44:93-100.
  • [79]Herrmann CS, Knight RT: Mechanisms of human attention: event-related potentials and oscillations. Neurosci Biobehav Rev 2001, 25:465-476.
  • [80]Varela F, Lachaux JP, Rodriguez E, Martinerie J: The brainweb: phase synchronization and large-scale integration. Nat Rev Neurosci 2001, 2:229-239.
  • [81]Brovelli A, Lachaux JP, Kahane P, Boussaoud D: High gamma frequency oscillatory activity dissociates attention from intention in the human premotor cortex. Neuroimage 2005, 28:154-164.
  • [82]Sambataro F, Murty VP, Callicott JH, Tan HY, Das S, Weinberger DR, Mattay VS: Age-related alterations in default mode network: impact on working memory performance. Neurobiol Aging 2010, 31:839-852.
  • [83]Charlton RA, Barrick TR, Lawes IN, Markus HS, Morris RG: White matter pathways associated with working memory in normal aging. Cortex 2010, 46:474-489.
  • [84]Damoiseaux JS, Beckmann CF, Arigita EJ, Barkhof F, Scheltens P, Stam CJ, Smith SM, Rombouts SA: Reduced resting-state brain activity in the "default network" in normal aging. Cereb Cortex 2008, 18:1856-1864.
  • [85]Golgeli A, Suer C, Ozesmi C, Dolu N, Ascioglu M, Sahin O: The effect of sex differences on event-related potentials in young adults. Int J Neurosci 1999, 99:69-77.
  • [86]Kober SE, Neuper C: Sex differences in human EEG theta oscillations during spatial navigation in virtual reality. Int J Psychophysiol 2010.
  • [87]Silas J, Levy JP, Nielsen MK, Slade L, Holmes A: Sex and individual differences in induced and evoked EEG measures of action observation. Neuropsychologia 2010, 48:2417-2426.
  • [88]Latta F, Leproult R, Tasali E, Hofmann E, Van Cauter E: Sex differences in delta and alpha EEG activities in healthy older adults. Sleep 2005, 28:1525-1534.
  • [89]Li J, Wang Y, Zhou R, Zhang H, Yang L, Wang B, Faraone SV: Association between polymorphisms in serotonin transporter gene and attention deficit hyperactivity disorder in Chinese Han subjects. Am J Med Genet B Neuropsychiatr Genet 2007, 144B:14-19.
  • [90]Yue W, Liu H, Zhang J, Zhang X, Wang X, Liu T, Liu P, Hao W: Association study of serotonin transporter gene polymorphisms with obstructive sleep apnea syndrome in Chinese Han population. Sleep 2008, 31:1535-1541.
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