It is now well-accepted that structural and biochemical alterations in brain circuitry during childhood and adolescence can affect learning, memory, and functional circuitry later in life. A common human single nucleotide polymorphism (SNP) in the BDNF prodomain that leads to valise-to-methionine substitution at codon 66 has provided insights into the role of BDNF in altered learning and memory, especially in the realm of fear-related processes. In vitro studies to date have suggested that this SNP acts as a loss of function mutation that impairs BDNF secretion. Thus, the abnormalities found in humans and knock-in mice with this SNP have been attributed to a loss of function model based on decreased bioavailability of mature BDNF. The potential function(s) of the isolated prodomain generated after proteolysis of proBDNF remain cryptic. Here, we provide evidence that the Met prodomain is secreted in an activity-dependent manner, acts as an independent ligand, and elicits antagonistic biological actions to mature BDNF, by activating an alternate set of receptors, p75NTR and SorCS2. Recently, we have made two key findings using the BDNF Met knock-in mouse that suggest that the Met prodomain affects the maturation of a specific brain circuit, leading to functional impairments in fear- based learning that is not evident with BDNF deficiency (BDNF+/- mice). We will directly test the hypothesis that the human Met prodomain of BDNF is a biologically active ligand that induces morphological neuronal remodeling, and explains the significant impact of this SNP on fear circuitry and function. We will identify the mechanisms by which Met prodomain signals through a p75/SorCS2 co-receptor complex to alter neuronal morphology in cultured neurons and affect the developing fear circuitry between the hippocampus and prefrontal cortex. Finally, we will determine the impact of the Met prodomain in fear extinction-related behaviors during a sensitive period for fear regulation during the transition into adolescence. Collectively, these studies are designed to investigate an additional potential mechanism by which the BDNF SNP may impact brain function. The hypotheses tested represent a significant reconceptualization of the biological actions of a key brain growth factor.

Public Health Relevance

Brain-derived neurotrophic factor (BDNF) plays a major role in circuits related to learning and memory. We propose that its cleaved prodomain, containing a human SNP, can act as a ligand that is secreted and elicits antagonistic actions to alter neuronal remodeling and explains the impact of this SNP on fear circuitry and function. Our studies represent a major reconceptualization of the biological actions of a brain growth factor, and initiates a new line of investigation in drug discovery to modulate function of the prodomain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052819-14
Application #
9624823
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mamounas, Laura
Project Start
2005-06-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
14
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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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
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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

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