BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity.
Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF(Val/Val)) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF(Met/Met)). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF(Met/Met) mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF(Met/Met) mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.
Department of Psychiatry, Weill Medical College of Cornell, New York, NY 10021, USA. Kevin_Bath@Brown.edu
Kevin G
KG
Bath
Deqiang Q
DQ
Jing
Iva
I
Dincheva
Christine C
CC
Neeb
Siobhan S
SS
Pattwell
Moses V
MV
Chao
Francis S
FS
Lee
Ipe
I
Ninan
D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism*; D004558:Electric Stimulation; D004797:Enzyme-Linked Immunosorbent Assay; D005473:Fluoxetine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics*; D008297:Male; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020813:Receptor, trkB / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014633:Valine / Q000235:genetics*
D019208:Brain-Derived Neurotrophic Factor; D001973:Bromodeoxyuridine; D005473:Fluoxetine; D005904:Glial Fibrillary Acidic Protein; D008715:Methionine; D020813:Receptor, trkB; D017367:Selective Serotonin Reuptake Inhibitors; D014633:Valine