Publication Type Academic Article
Authors Giza J, Kim J, Meyer H, Anastasia A, Dincheva I, Zheng C, Lopez K, Bains H, Yang J, Bracken C, Liston C, Jing D, Hempstead B, Lee F
Journal Neuron
Volume 99
Issue 1
Pagination 163-178.e6
Date Published 06/14/2018
ISSN 1097-4199
Keywords Brain-Derived Neurotrophic Factor, CA1 Region, Hippocampal, Dendritic Spines, Extinction, Psychological, Fear, Neurons, Synapses
Abstract 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/p75NTR 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 BdnfMet/Met 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 BDNFMet/Met 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.
DOI 10.1016/j.neuron.2018.05.024
PubMed ID 29909994
PubMed Central ID PMC6054457
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