The BDNF gene Val66Met single nucleotide polymorphism interacts with chronic CORT exposure to determine affective- and anxiety-related behavior (#139)
Background
Brain-Derived Neurotrophic Factor (BDNF) is a
promoter of neuronal plasticity. The BDNF gene
Val66Met polymorphism disrupts activity-dependent secretion of BDNF and has
been, variably, associated with anxiety and mood disorders. It has been
suggested that stress hormones, which further down-regulate transcription of
BDNF, may mediate the involvement of the Val66Met polymorphism in these
disorders. However, this hypothesis lacks experimental validation. We therefore
sought to model the long-term effects of chronic stress by using a novel Val66Met
knock-in mouse that is genetically modified to express
human BDNF (hBDNF) via endogenous mouse promoters.
Methods
To simulate stress, corticosterone
(CORT) was administered in the water of wildtype (hBDNFVal/Val) and mutant (hBDNFVal/Met, hBDNFMet/Met) mice at a dose of
25mg/L from 6 to 9 weeks of age. Mice underwent
behavioral testing two weeks later for fear-dependent memory, using fear
conditioning and an extinction learning protocol, for anxiety using the light-dark
box (LDB), and for depressive behavior using the forced-swim test (FST).
Results
At baseline, memory of fear was disrupted in hBDNFMet/Met mice
relative to hBDNFVal/Val controls. However, this phenotype was
reversed by a BDNF-CORT interaction which selectively enhanced memory of fear in
hBDNFMet/Met mice. While extinction learning was unaffected at
baseline, chronic CORT exposure selectively increased rate of extinction learning in hBDNFVal/Met
and hBDNFMet/Met mice relative to hBDNFVal/Val
controls. There was no BDNF-mediated anxiety-like phenotype on the LDB. The FST
revealed a depressive-like phenotype of hBDNFMet/Met mice at
baseline, while the chronic CORT treatment selectively increased the
depressive-like behavior of hBDNFVal/Val controls only.
Conclusion
We report that chronic CORT exposure interacts with the BDNF
Val66Met polymorphism to selectively modify affective- and anxiety-related
behavior. This novel gene-environment interaction highlights how affective- and
anxiety-related behavior is variably regulated by both BDNF and CORT exposure,
having implications for the treatment and prevention of stress-inducible psychiatric
disorders.