Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 306 (5697): 879-881

Copyright © 2004 by the American Association for the Advancement of Science

Early-Life Blockade of the 5-HT Transporter Alters Emotional Behavior in Adult Mice

Mark S. Ansorge,1,2,3 Mingming Zhou,2,3 Alena Lira,2,3 René Hen,2,4 Jay A. Gingrich2,3*

Abstract: Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

1 Sackler Institute for Developmental Psychobiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
2 Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
3 Department of Developmental Psychobiology, New York State Psychiatric Institute, New York, NY 10032, USA.
4 Department of Neurobiology and Behavior, New York State Psychiatric Institute, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: jag46{at}

Variation in Key Genes of Serotonin and Norepinephrine Function Predicts Gamma-Band Activity during Goal-Directed Attention.
S. Enge, M. Fleischhauer, K.-P. Lesch, A. Reif, and A. Strobel (2014)
Cereb Cortex 24, 1195-1205
   Abstract »    Full Text »    PDF »
Prenatal Antidepressant Exposure: Clinical and Preclinical Findings.
C. H. Bourke, Z. N. Stowe, and M. J. Owens (2014)
Pharmacol. Rev. 66, 435-465
   Abstract »    Full Text »    PDF »
Fluoxetine Exposure during Adolescence Alters Responses to Aversive Stimuli in Adulthood.
S. D. Iniguez, L. F. Alcantara, B. L. Warren, L. M. Riggs, E. M. Parise, V. Vialou, K. N. Wright, G. Dayrit, S. J. Nieto, M. B. Wilkinson, et al. (2014)
J. Neurosci. 34, 1007-1021
   Abstract »    Full Text »    PDF »
Valproic acid silencing of ascl1b/Ascl1 results in the failure of serotonergic differentiation in a zebrafish model of fetal valproate syndrome.
J. Jacob, V. Ribes, S. Moore, S. C. Constable, N. Sasai, S. S. Gerety, D. J. Martin, C. P. Sergeant, D. G. Wilkinson, and J. Briscoe (2014)
Dis. Model. Mech. 7, 107-117
   Abstract »    Full Text »    PDF »
Reply: Risks of untreated depression outweigh any risks of SSRIs.
A. C. Urato and A. D. Domar (2013)
Hum. Reprod. 28, 1146-1148
   Full Text »    PDF »
Looking beyond the DNA sequence: the relevance of DNA methylation processes for the stress-diathesis model of depression.
L. Booij, D. Wang, M. L. Levesque, R. E. Tremblay, and M. Szyf (2013)
Phil Trans R Soc B 368, 20120251
   Abstract »    Full Text »    PDF »
The serotonergic system in mood disorders and suicidal behaviour.
J. J. Mann (2013)
Phil Trans R Soc B 368, 20120537
   Abstract »    Full Text »    PDF »
The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond.
A. D. Domar, V. A. Moragianni, D. A. Ryley, and A. C. Urato (2013)
Hum. Reprod. 28, 160-171
   Abstract »    Full Text »    PDF »
Prenatal exposure to antidepressants and depressed maternal mood alter trajectory of infant speech perception.
W. M. Weikum, T. F. Oberlander, T. K. Hensch, and J. F. Werker (2012)
PNAS 109, 17221-17227
   Abstract »    Full Text »    PDF »
Critical period for acoustic preference in mice.
E.-J. Yang, E. W. Lin, and T. K. Hensch (2012)
PNAS 109, 17213-17220
   Abstract »    Full Text »    PDF »
The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms.
P. R. Albert, C. Benkelfat, and L. Descarries (2012)
Phil Trans R Soc B 367, 2378-2381
   Abstract »    Full Text »    PDF »
Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.
J. Veenstra-VanderWeele, C. L. Muller, H. Iwamoto, J. E. Sauer, W. A. Owens, C. R. Shah, J. Cohen, P. Mannangatti, T. Jessen, B. J. Thompson, et al. (2012)
PNAS 109, 5469-5474
   Abstract »    Full Text »    PDF »
MAGE-D1 Regulates Expression of Depression-Like Behavior through Serotonin Transporter Ubiquitylation.
A. Mouri, A. Sasaki, K. Watanabe, C. Sogawa, S. Kitayama, T. Mamiya, Y. Miyamoto, K. Yamada, Y. Noda, and T. Nabeshima (2012)
J. Neurosci. 32, 4562-4580
   Abstract »    Full Text »    PDF »
5-HT7R/G12 Signaling Regulates Neuronal Morphology and Function in an Age-Dependent Manner.
F. Kobe, D. Guseva, T. P. Jensen, A. Wirth, U. Renner, D. Hess, M. Muller, L. Medrihan, W. Zhang, M. Zhang, et al. (2012)
J. Neurosci. 32, 2915-2930
   Abstract »    Full Text »    PDF »
Perinatal Citalopram Exposure Selectively Increases Locus Ceruleus Circuit Function in Male Rats.
R. D. Darling, L. Alzghoul, J. Zhang, N. Khatri, I. A. Paul, K. L. Simpson, and R. C. S. Lin (2011)
J. Neurosci. 31, 16709-16715
   Abstract »    Full Text »    PDF »
Perinatal antidepressant exposure alters cortical network function in rodents.
K. L. Simpson, K. J. Weaver, E. de Villers-Sidani, J. Y.- F. Lu, Z. Cai, Y. Pang, F. Rodriguez-Porcel, I. A. Paul, M. Merzenich, and R. C. S. Lin (2011)
PNAS 108, 18465-18470
   Abstract »    Full Text »    PDF »
Chronic 5-HT Transporter Blockade Reduces DA Signaling to Elicit Basal Ganglia Dysfunction.
E. Morelli, H. Moore, T. J. Rebello, N. Gray, K. Steele, E. Esposito, J. A. Gingrich, and M. S. Ansorge (2011)
J. Neurosci. 31, 15742-15750
   Abstract »    Full Text »    PDF »
Serotonin Transporter Occupancy in Rats Exposed to Serotonin Reuptake Inhibitors In Utero or via Breast Milk.
C. F. Capello, C. H. Bourke, J. C. Ritchie, Z. N. Stowe, D. J. Newport, A. Nemeroff, and M. J. Owens (2011)
J. Pharmacol. Exp. Ther. 339, 275-285
   Abstract »    Full Text »    PDF »
Roles of the placenta in fetal brain development.
L. M. Zeltser and R. L. Leibel (2011)
PNAS 108, 15667-15668
   Full Text »    PDF »
SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation.
A. S. Kristensen, J. Andersen, T. N. Jorgensen, L. Sorensen, J. Eriksen, C. J. Loland, K. Stromgaard, and U. Gether (2011)
Pharmacol. Rev. 63, 585-640
   Abstract »    Full Text »    PDF »
The truth about genetic variation in the serotonin transporter gene and response to stress and medication.
P. McGuffin, S. Alsabban, and R. Uher (2011)
The British Journal of Psychiatry 198, 424-427
   Abstract »    Full Text »    PDF »
Developmental Outcomes of Children Exposed to Antidepressants in Pregnancy.
M. Galbally, A. J. Lewis, and A. Buist (2011)
Australian and New Zealand Journal of Psychiatry 45, 393-399
   Abstract »    Full Text »    PDF »
Serotonin-1A Autoreceptors Are Necessary and Sufficient for the Normal Formation of Circuits Underlying Innate Anxiety.
J. W. Richardson-Jones, C. P. Craige, T. H. Nguyen, H. F. Kung, A. M. Gardier, A. Dranovsky, D. J. David, B. P. Guiard, S. G. Beck, R. Hen, et al. (2011)
J. Neurosci. 31, 6008-6018
   Abstract »    Full Text »    PDF »
Temporal control of a dendritogenesis-linked gene via REST-dependent regulation of nuclear factor I occupancy.
W. Wang, Y. Shin, M. Shi, and D. L. Kilpatrick (2011)
Mol. Biol. Cell 22, 868-879
   Abstract »    Full Text »    PDF »
What can whole genome expression data tell us about the ecology and evolution of personality?.
A. M. Bell and N. Aubin-Horth (2010)
Phil Trans R Soc B 365, 4001-4012
   Abstract »    Full Text »    PDF »
Forebrain overexpression of CK1{delta} leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD.
M. Zhou, H. Rebholz, C. Brocia, J. L. Warner-Schmidt, A. A. Fienberg, A. C. Nairn, P. Greengard, and M. Flajolet (2010)
PNAS 107, 4401-4406
   Abstract »    Full Text »    PDF »
Fetal Exposure to Antidepressants and Normal Milestone Development at 6 and 19 Months of Age.
L. H. Pedersen, T. B. Henriksen, and J. Olsen (2010)
Pediatrics 125, e600-e608
   Abstract »    Full Text »    PDF »
A neurochemical approach to valuation sensitivity over gains and losses.
S. Zhong, S. Israel, H. Xue, P. C. Sham, R. P. Ebstein, and S. H. Chew (2009)
Proc R Soc B 276, 4181-4188
   Abstract »    Full Text »    PDF »
Serotonin Transporter Availability in the Amygdala and Bed Nucleus of the Stria Terminalis Predicts Anxious Temperament and Brain Glucose Metabolic Activity.
J. A. Oler, A. S. Fox, S. E. Shelton, B. T. Christian, D. Murali, T. R. Oakes, R. J. Davidson, and N. H. Kalin (2009)
J. Neurosci. 29, 9961-9966
   Abstract »    Full Text »    PDF »
X11-Like Protein Deficiency Is Associated with Impaired Conflict Resolution in Mice.
Y. Sano, V. G. Ornthanalai, K. Yamada, C. Homma, H. Suzuki, T. Suzuki, N. P. Murphy, and S. Itohara (2009)
J. Neurosci. 29, 5884-5896
   Abstract »    Full Text »    PDF »
The ethics of paediatric anti-depressant use: erring on the side of caution.
M C Shearer and S L Bermingham (2008)
J. Med. Ethics 34, 710-714
   Abstract »    Full Text »    PDF »
Lasting Syndrome of Depression Produced by Reduction in Serotonin Uptake during Postnatal Development: Evidence from Sleep, Stress, and Behavior.
D. Popa, C. Lena, C. Alexandre, and J. Adrien (2008)
J. Neurosci. 28, 3546-3554
   Abstract »    Full Text »    PDF »
Inhibition of Serotonin But Not Norepinephrine Transport during Development Produces Delayed, Persistent Perturbations of Emotional Behaviors in Mice.
M. S. Ansorge, E. Morelli, and J. A. Gingrich (2008)
J. Neurosci. 28, 199-207
   Abstract »    Full Text »    PDF »
Correlation between the SERT binding densities in hypothalamus and amygdala in cloninger type 1 and 2 alcoholics.
M. Storvik, T. Haukijarvi, E. Tupala, and J. Tiihonen (2008)
Alcohol Alcohol. 43, 25-30
   Abstract »    Full Text »    PDF »
Vmat2 Heterozygous Mutant Mice Display a Depressive-Like Phenotype.
M. Fukui, R. M. Rodriguiz, J. Zhou, S. X. Jiang, L. E. Phillips, M. G. Caron, and W. C. Wetsel (2007)
J. Neurosci. 27, 10520-10529
   Abstract »    Full Text »    PDF »
Impaired Stress-Coping and Fear Extinction and Abnormal Corticolimbic Morphology in Serotonin Transporter Knock-Out Mice.
C. L. Wellman, A. Izquierdo, J. E. Garrett, K. P. Martin, J. Carroll, R. Millstein, K.-P. Lesch, D. L. Murphy, and A. Holmes (2007)
J. Neurosci. 27, 684-691
   Abstract »    Full Text »    PDF »
Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice..
N. V. Weisstaub, M. Zhou, A. Lira, E. Lambe, J. Gonzalez-Maeso, J.-P. Hornung, E. Sibille, M. Underwood, S. Itohara, W. T. Dauer, et al. (2006)
Science 313, 536-540
   Abstract »    Full Text »    PDF »
Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter..
C. Alexandre, D. Popa, V. Fabre, S. Bouali, P. Venault, K.-P. Lesch, M. Hamon, and J. Adrien (2006)
J. Neurosci. 26, 5554-5564
   Abstract »    Full Text »    PDF »
Contribution of 5-HT2 Receptor Subtypes to Sleep-Wakefulness and Respiratory Control, and Functional Adaptations in Knock-Out Mice Lacking 5-HT2A Receptors.
D. Popa, C. Lena, V. Fabre, C. Prenat, J. Gingrich, P. Escourrou, M. Hamon, and J. Adrien (2005)
J. Neurosci. 25, 11231-11238
   Abstract »    Full Text »    PDF »
Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase.
H. C. Prasad, C.-B. Zhu, J. L. McCauley, D. J. Samuvel, S. Ramamoorthy, R. C. Shelton, W. A. Hewlett, J. S. Sutcliffe, and R. D. Blakely (2005)
PNAS 102, 11545-11550
   Abstract »    Full Text »    PDF »
Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice.
T. Esaki, M. Cook, K. Shimoji, D. L. Murphy, L. Sokoloff, and A. Holmes (2005)
PNAS 102, 5582-5587
   Abstract »    Full Text »    PDF »
Possible Sleeper Effects of an SSRI: An Animal Study.
Journal Watch Psychiatry 2005, 3
   Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882