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

Neuron. 2018 Jul 11;99(1):163-178.e6. doi: 10.1016/j.neuron.2018.05.024. Epub 2018 Jun 14.

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.

Keywords: BDNF; SorCS2; fear extinction; fiber photometry; p75(NTR); peri-adolescence; polymorphism; prodomain; synapse elimination; ventral CA1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics*
  • CA1 Region, Hippocampal / pathology*
  • CA1 Region, Hippocampal / physiopathology
  • Dendritic Spines / pathology*
  • Extinction, Psychological*
  • Fear*
  • Mice
  • Neurons / pathology*
  • Polymorphism, Single Nucleotide
  • Synapses / pathology*

Substances

  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor