The BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior.

Authors:
Joanna I Giza
Joanna I Giza
Yale University
Jihye Kim
Jihye Kim
Graduate School of East-West Medical Science
South Korea
Heidi C Meyer
Heidi C Meyer
University of California
United States
Agustin Anastasia
Agustin Anastasia
University of Sydney at Royal North Shore Hospital
Australia
Iva Dincheva
Iva Dincheva
Weill Cornell Medical College
United States
Katherine Lopez
Katherine Lopez
National Institute of Mental Health
United States

Neuron 2018 Jul 14;99(1):163-178.e6. Epub 2018 Jun 14.

Department of Psychiatry, Weill Cornell Medicine, New York, NY 10065, USA; Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

A human variant in the BDNF gene (Val66Met; rs6265) is associated with impaired fear extinction. Using super-resolution imaging, we demonstrate that the BDNF Met prodomain disassembles dendritic spines and eliminates synapses in hippocampal neurons. In vivo, ventral CA1 (vCA1) hippocampal neurons undergo similar morphological changes dependent on their transient co-expression of a SorCS2/p75 receptor complex during peri-adolescence. BDNF Met prodomain infusion into the vCA1 during this developmental time frame reduces dendritic spine density and prelimbic (PL) projections, impairing cued fear extinction. Adolescent Bdnf mice display similar spine and PL innervation deficits. Using fiber photometry, we found that, in wild-type mice, vCA1 neurons projecting to the PL encode extinction by enhancing neural activity in threat anticipation and rapidly subsiding their response. This adaptation is absent in BDNF mice. We conclude that the BDNF Met prodomain renders vCA1-PL projection neurons underdeveloped, preventing their capacity for subsequent circuit modulation necessary for fear extinction. VIDEO ABSTRACT.

Abstract Video

A Unique Ligand Limiting Neuronal Adaptations Necessary to Extinguish Fear


Source: Cell Press

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http://dx.doi.org/10.1016/j.neuron.2018.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054457PMC

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July 2018
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