Background
A polymorphism in the serotonin transporter (5-HTT) gene modulates the association
between adverse early experiences and risk for major depression in adulthood. Although
human imaging studies have begun to elucidate the neural circuits involved in the
5-HTT × environment risk factor, a molecular understanding of this phenomenon is lacking.
Such an understanding might help to identify novel targets for the diagnosis and therapy
of mood disorders. To address this need, we developed a gene-environment screening
paradigm in the mouse.
Methods
We established a mouse model in which a heterozygous null mutation in 5-HTT moderates
the effects of poor maternal care on adult anxiety and depression-related behavior.
Biochemical analysis of brains from these animals was performed to identify molecular
substrates of the gene, environment, and gene × environment effects.
Results
Mice experiencing low maternal care showed deficient γ-aminobutyric acid–A receptor
binding in the amygdala and 5-HTT heterozygous null mice showed decreased serotonin
turnover in hippocampus and striatum. Strikingly, levels of brain-derived neurotrophic
factor (BDNF) messenger RNA in hippocampus were elevated exclusively in 5-HTT heterozygous
null mice experiencing poor maternal care, suggesting that developmental programming
of hippocampal circuits might underlie the 5-HTT × environment risk factor.
Conclusions
These findings demonstrate that serotonin plays a similar role in modifying the long-term
behavioral effects of rearing environment in diverse mammalian species and identifies
BDNF as a molecular substrate of this risk factor.
Key Words
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References
- Gene-environment interaction and the genetics of depression.J Psychiatry Neurosci. 2004; 29: 174-184
- Adverse childhood experiences and the risk of depressive disorders in adulthood.J Affect Disord. 2004; 82: 217-225
- A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety.Mol Psychiatry. 2004; 9: 197-202
- Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.Science. 2003; 301: 386-389
- Neural correlates of epigenesis.Proc Natl Acad Sci U S A. 2006; 103: 16033-16038
- Serotonin transporter genetic variation and the response of the human amygdala.Science. 2002; 297: 400-403
- Beyond affect: A role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task.Proc Natl Acad Sci U S A. 2005; 102: 12224-12229
- 5-HTTLPR polymorphism impacts human cingulated-amygdala interactions: A genetic susceptibility mechanism for depression.Nat Neurosci. 2005; 8: 828-834
- Identifying interactions between genes and early environment in the mouse.Genes Brain Behav. 2006; 5: 189-199
- Emotional reactivity in mice may not be inherited but influenced by parents.Physiol Behav. 2004; 80: 465-474
- Do early-life events permanently alter behavioral and hormonal responses to stressors?.Int J Dev Neurosci. 1998; 16: 149-164
- Child’s stress hormone levels correlate with mother’s socioeconomic status and depressive state.Biol Psychiatry. 2000; 48: 976-980
- Nongenomic transmission across generations of maternal behavior and stress responses in the rat.Science. 1999; 286: 1155-1158
- Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice.Neuropsychopharmacology. 2004; 29: 1344-1352
- A review and meta-analysis of the genetic epidemiology of anxiety disorders.Am J Psychiatry. 2001; 158: 1568-1578
- Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter.Neuropsychopharmacology. 2002; 27: 914-923
- Mice lacking the serotonin transporter exhibit 5-HT1a receptor-mediated abnormalities in tests for anxiety-like behavior.Neuropsychopharmacology. 2003; 28: 2077-2088
- Abnormal anxiety-related behavior in serotonin transporter null mutant mice: The influence of genetic background.Genes Brain Behav. 2003; 2: 365-380
- Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice.Mol Pharmacol. 1998; 53: 649-655
- Tryptophan hydroxylase-2 controls brain serotonin synthesis.Science. 2004; 305: 217
- Mice lacking brain-derived neurotrophic factor develop with sensory deficits.Nature. 1994; 368: 147-150
- The tail suspension test: A new method for screening antidepressants in mice.Psychopharmacology (Berl). 1985; 85: 367-370
- Suppression of conditioned responses to ambiguous cues by pharmacogenetic inhibition of dentate gyrus granule cells.Nat Neurosci. 2007; 7: 896-902
- Dramatic brain aminergic deficit in a genetic mouse model of phenylketonuria.Neuroreport. 2000; 11: 1361-1364
- Selective in vitro and in vivo binding of [(125)I]ADAM to serotonin transporters in rat brain.Synapse. 2000; 4: 403-412
- Serotonin 1A receptor acts during development to establish normal anxiety-like behavior in the adult.Nature. 2002; 416: 396-400
- Regulation of BDNF and trkB in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.J Neurosci. 1995; 15: 7539-7547
- Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice.Behav Brain Res. 2006; 175: 43-50
- The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice.Neurosci Biobehav Rev. 2005; 29: 571-625
- Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues.Nat Neurosci. 1999; 2: 833-839
- Interpretive cues and ambiguity in generalized anxiety disorder.Behav Res Ther. 2004; 42: 881-892
- BDNF and activity-dependent synaptic modulation.Learn Mem. 2003; 10: 86-98
- Exploring the relationship between serotonin and brain-derived neurotrophic factor: Analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression.J Neurosci Methods. 2004; 140: 81-89
- Maternal care, hippocampal synaptogenesis and cognitive development in rats.Nat Neurosci. 2000; 3: 799-806
- Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing.Cereb Cortex. 2007; 5: 1160-1163
- Effects of centrally administered anxiolytic compounds in animal models of anxiety.Neurosci Biobehav Rev. 1999; 23: 591-613
- Molecular, pharmacological and functional diversity of 5-HT receptors.Pharmacol Biochem Behav. 2002; 71: 533-554
- Serotonergic regulation of membrane potential in developing rat prefrontal cortex: Coordinated expression of 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT7 receptors.J Neurosci. 2004; 24: 4807-4817
- The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.Cell. 2003; 112: 257-269
- Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects.Proc Natl Acad Sci U S A. 2006; 103: 13208-13213
- Levels of neurotrophic factors in the hippocampus and amygdala correlate with anxiety- and fear-related behavior in C57BL6 mice.J Neural Transm. 2007; 4: 431-444
Article Info
Publication History
Published online: October 22, 2007
Accepted:
August 24,
2007
Received in revised form:
July 19,
2007
Received:
April 7,
2007
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
