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

TitleThe BDNF Val66Met Prodomain Disassembles Dendritic Spines Altering Fear Extinction Circuitry and Behavior.
Publication TypeJournal Article
Year of Publication2018
AuthorsGiza JI, Kim J, Meyer HC, Anastasia A, Dincheva I, Zheng CI, Lopez K, Bains H, Yang J, Bracken C, Liston C, Jing D, Hempstead BL, Lee FS
Date Published2018 Jul 11

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.

Alternate JournalNeuron
PubMed ID29909994
PubMed Central IDPMC6054457
Grant ListG12 MD007599 / MD / NIMHD NIH HHS / United States
R01 MH109685 / MH / NIMH NIH HHS / United States
R01 NS052819 / NS / NINDS NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States