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

Summary 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 NTR 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 Met/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 BDNF Met/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