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 x 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 x environment effects. RESULTS: Mice experiencing low maternal care showed deficient gamma-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 x 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.
Identifying molecular substrates in a mouse model of the serotonin transporter x environment risk factor for anxiety and depression / Carola, Valeria; Frazzetto, G; Pascucci, Tiziana; Audero, E; PUGLISI ALLEGRA, Stefano; Cabib, Simona; Lesch, Kp; Gross, C.. - In: BIOLOGICAL PSYCHIATRY. - ISSN 0006-3223. - 63:9(2008), pp. 840-846. [10.1016/j.biopsych.2007.08.013]
Identifying molecular substrates in a mouse model of the serotonin transporter x environment risk factor for anxiety and depression.
CAROLA, Valeria;PASCUCCI, Tiziana;PUGLISI ALLEGRA, Stefano;CABIB, Simona;
2008
Abstract
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 x 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 x environment effects. RESULTS: Mice experiencing low maternal care showed deficient gamma-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 x 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.File | Dimensione | Formato | |
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