Poster Presentation The International Congress of Neuroendocrinology 2014

The BDNF gene Val66Met single nucleotide polymorphism interacts with chronic CORT exposure to determine affective- and anxiety-related behavior (#139)

Michael Notaras 1 2 , Rachel Hill 1 , Joseph Gogos 3 4 , Maarten van den Buuse 1
  1. Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
  2. Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
  3. Department of Biophysics, Columbia University, New York, United States of America
  4. Department of Neuroscience, Columbia University, New York, United States of America

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.