title: The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex.
abstract: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is a common human single nucleotide polymorphism (SNP) that affects the regulated release of BDNF, and has been implicated in affective disorders and cognitive dysfunction. A decreased activation of the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for the regulation of affective behaviors, has been described in BDNF(Met) carriers. However, it is unclear whether and how the Val66Met polymorphism affects the IL-mPFC synapses. Here, we report that spike timing-dependent plasticity (STDP) was absent in the IL-mPFC pyramidal neurons from BDNF(Met/Met) mice, a mouse that recapitulates the specific phenotypic properties of the human BDNF Val66Met polymorphism. Also, we observed a decrease in NMDA and GABA receptor-mediated synaptic transmission in the pyramidal neurons of BDNF(Met/Met) mice. While BDNF enhanced non-NMDA receptor transmission and depressed GABA receptor transmission in the wild-type mice, both effects were absent in BDNF(Met/Met) mice after BDNF treatment. Indeed, exogenous BDNF reversed the deficits in STDP and NMDA receptor transmission in BDNF(Met/Met) neurons. BDNF-mediated selective reversal of the deficit in plasticity and NMDA receptor transmission, but its lack of effect on GABA and non-NMDA receptor transmission in BDNF(Met/Met) mice, suggests separate mechanisms of Val66Met polymorphism upon synaptic transmission. The effect of the Val66Met polymorphism on synaptic transmission and plasticity in the IL-mPFC represents a mechanism to account for this impact of SNP on affective disorders and cognitive dysfunction.
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Siobhan S
authors.initials: SS
authors.lastname: Pattwell
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Bath
authors.forename: Rosalia
authors.initials: R
authors.lastname: Perez-Castro
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: Ipe
authors.initials: I
authors.lastname: Ninan
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D005239:Fear / Q000502:physiology; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology*; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D014633:Valine / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D008715:Methionine; D014633:Valine