Identifying molecular substrates in a mouse model of the serotonin transporter x environment risk factor for anxiety and depression.
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.
Carola
Valeria
V
Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo, Rome, Italy.
Frazzetto
Giovanni
G
Pascucci
Tiziana
T
Audero
Enrica
E
Puglisi-Allegra
Stefano
S
Cabib
Simona
S
Lesch
Klaus-Peter
KP
Gross
Cornelius
C
D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D003433:Crosses, Genetic; D004252:DNA Mutational Analysis; D003863:Depression / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006579:Heterozygote; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D017403:In Situ Hybridization; D008297:Male; D008425:Maternal Behavior; D051379:Mice; D008815:Mice, Inbred Strains; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012931:Social Environment
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin