Chronic Activation of the Glucocorticoid Receptor Alters Memory Function of Val66Met Polymorphism Knock-in hBDNF Mice
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1
University of Melbourne, Florey Department of Neuroscience and Mental Health, Australia
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2
Florey Institute of Neuroscience and Mental Health, Australia
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3
Columbia University, Department of Physiology and Cellular Biophysics, United States of America
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4
Columbia University, Department of Neuroscience, United States of America
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5
University of Melbourne, Department of Pharmacology and Therapeutics, Australia
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6
La Trobe Institute of Molecular Science, Australia
Background Brain-Derived Neurotrophic Factor (BDNF) promotes neuronal development, differentiation and plasticity. A functional variant termed the Val66Met single nucleotide polymorphism (SNP) disrupts activity-dependent secretion and subcellular translocation of BDNF. The Val66Met SNP has been associated with hippocampal function but results from human studies remain inconsistent. Here we investigate the long-term effects of chronic stress on memory using a Val66Met knock-in mouse model that has been genetically modified to express human BDNF (hBDNF) via endogenous mouse promoters. Methods The stress hormone corticosterone (CORT) was administered in the drinking water of mice at a dose of 25mg/L from 6 to 9 weeks of age. Memory was tested in weeks 11 to 12 using contextual and cued fear conditioning (FC) as well as the Y-maze, while extinction learning was examined in a FC naïve cohort. Results At baseline, a significant genotype x arm interaction was detected on the Y-maze indicating that hBDNFMet/Met mice had disrupted short-term spatial memory performance. This deficit, however, was rescued by the chronic CORT treatment which restored the memory performance of hBDNFMet/Met mice to levels consistent with hBDNFVal/Val controls. Memory of fear was similarly disrupted in hBDNFMet/Met mice at baseline, but was also rescued through an interaction with CORT. While this BDNF-CORT interaction accounted for up to 16.32% of the variability of fear memory, only subtle differences in fear extinction learning were detected between groups. Conclusion We report that chronic stress interacts with the BDNF Val66Met SNP to selectively modify memory function. In particular, while hippocampal function of hBDNFMet/Met mice is disrupted at baseline this deficit is rescued into adulthood by chronic glucocorticoid receptor activation during adolescence. This novel gene-environment interaction highlights how adult memory function is variably regulated by both BDNF and history of stress.
Keywords:
Corticosterone,
Fear,
Memory,
BDNF,
stress,
Glucocorticoid receptor,
Hippocampal function,
val66met,
hBDNF Mice
Conference:
XII International Conference on Cognitive Neuroscience (ICON-XII), Brisbane, Queensland, Australia, 27 Jul - 31 Jul, 2014.
Presentation Type:
Poster
Topic:
Memory and Learning
Citation:
Notaras
M,
Hill
R,
Gogos
J and
Van Den Buuse
M
(2015). Chronic Activation of the Glucocorticoid Receptor Alters Memory Function of Val66Met Polymorphism Knock-in hBDNF Mice.
Conference Abstract:
XII International Conference on Cognitive Neuroscience (ICON-XII).
doi: 10.3389/conf.fnhum.2015.217.00263
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Received:
19 Feb 2015;
Published Online:
24 Apr 2015.
*
Correspondence:
Mr. Michael Notaras, University of Melbourne, Florey Department of Neuroscience and Mental Health, Melbourne, Australia, mnotaras@student.unimelb.edu.au