Brain derived neurotrophic factor (BDNF) plays critical roles in vertebrate nervous system development and function. Recently, a single nucleotide polymorphism (Val66Met) in the BDNF gene leading to a prodomain substitution at position 66 from a valine (Val) to methionme (Met) has been shown to lead in humans to hippocampal dependent memory impairments and susceptibility to neuropsychiatric disorders. This BDNF polymorphism represents the first alteration in a neurotrophin that has been linked to clinical pathology. Less is known about the molecular mechanisms underlying altered variant BDNF (BDNFMet) functioning. When overexpressed in hippocampal neurons, BDNFMet has reduced activity dependent secretion, suggesting the presence of a specific signal in the BDNF prodomain that is required for efficient BDNF trafficking to the regulated secretory pathway. Preliminary studies suggest the hypothesis that BDNFMet aberrantly engages the highly specialized biochemical mechanisms that regulate BDNF trafficking to secretory pathways, which are critical determinants of BDNF's biological responses. The proposed studies are designed to identify specific proteins that regulate aberrant BDNFMet trafficking, and to examine the in vivo consequences on hippocampal structure and function. Experiments in this proposal will primarily utilize a novel transgenic knock-in mouse expressing an epitope tagged version of variant BDNF (BDNF 9 e) to enable assessment of BDNFMet trafficking events under endogenously expressed conditions and analysis of in vivo consequences on hippocampal structure and function.
The Specific Aims of the proposed studies are to 1) define the trafficking defect and functional consequences in neurons endogenously expressing BDNFMet, 2) identify proteins that are involved in aberrant BDNFMet trafficking, and 3) determine the in vivo consequences of BDNFMet on hippocampal function. These studies will contribute to a fundamental molecular understanding of the mechanisms that underlie aberrant BDNFMet trafficking in neurons, and directly address the physiological relevance of this variant BDNF on hippocampal function.
|Gray, J D; Rubin, T G; Kogan, J F et al. (2018) Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice. Mol Psychiatry 23:904-913|
|Giza, Joanna I; Kim, Jihye; Meyer, Heidi C et al. (2018) The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior. Neuron 99:1356|
|Giza, Joanna I; Kim, Jihye; Meyer, Heidi C et al. (2018) The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior. Neuron 99:163-178.e6|
|Dincheva, Iva; Yang, Jianmin; Li, Anfei et al. (2017) Effect of Early-Life Fluoxetine on Anxiety-Like Behaviors in BDNF Val66Met Mice. Am J Psychiatry 174:1203-1213|
|Marrocco, Jordan; Petty, Gordon H; Ríos, Mariel B et al. (2017) A sexually dimorphic pre-stressed translational signature in CA3 pyramidal neurons of BDNF Val66Met mice. Nat Commun 8:808|
|Jing, Deqiang; Lee, Francis S; Ninan, Ipe (2017) The BDNF Val66Met polymorphism enhances glutamatergic transmission but diminishes activity-dependent synaptic plasticity in the dorsolateral striatum. Neuropharmacology 112:84-93|
|Song, M; Martinowich, K; Lee, F S (2017) BDNF at the synapse: why location matters. Mol Psychiatry 22:1370-1375|
|Amadio, Patrizia; Colombo, Gualtiero I; Tarantino, Eva et al. (2017) BDNFVal66met polymorphism: a potential bridge between depression and thrombosis. Eur Heart J 38:1426-1435|
|Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra et al. (2016) Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice. Neuropsychopharmacology 41:3070-3079|
|Hill, Matthew N; Lee, Francis S (2016) Endocannabinoids and Stress Resilience: Is Deficiency Sufficient to Promote Vulnerability? Biol Psychiatry 79:792-793|
Showing the most recent 10 out of 57 publications