BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity.

K.G. Bath; D.S. Jing; S.S. Pattwell; M.V. Chao; F.S. Lee; I. Ninan
Society for Neuroscience. 2010.


Recently, a single nucleotide polymorphism (SNP) in the bdnf gene (BDNF Val66Met) has been linked with the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates phenotypes of human BDNF Val66Met carriers and leads to elevated levels of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. The mechanism underlying impaired SSRI response in BDNFMet/Met mice has remained unclear. A prominent hypothesis is that SSRI-induced augmentation of BDNF expression and the beneficial trophic effects of BDNF on neural plasticity (e.g. neurogenesis and LTP) are critical components for drug response. BDNFMet/Met mice had decreased baseline BDNF protein levels in the hippocampus that did not increase following fluoxetine treatment. We tested for impairments in hippocampus plasticity in adult male control and chronic fluoxetine treated homozygous BDNFMet/Met and wild-type mice. BDNFMet/Met mice also had impairments in the survival of newly born cells and synaptic long-term potentiation (LTP) in the hippocampus; effects that remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and neural plasticity provide a mechanistic basis by which decreased BDNF bioavailability conferred by this SNP may impair efficacy of SSRI drug treatment.