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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2018-07, Vol.99 (1), p.163-178.e6
• Main Authors: Giza, Joanna I., Kim, Jihye, Meyer, Heidi C., Anastasia, Agustin, Dincheva, Iva, Zheng, Crystal I., Lopez, Katherine, Bains, Henrietta, Yang, Jianmin, Bracken, Clay, Liston, Conor, Jing, Deqiang, Hempstead, Barbara L., Lee, Francis S.
• Format: Article
• Language: English
• Subjects: Adolescence; Adolescents; Animals; Anxiety; BDNF; Bioavailability; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - genetics; CA1 Region, Hippocampal - pathology; CA1 Region, Hippocampal - physiopathology; Child development; Dendritic spines; Dendritic Spines - pathology; Extinction; Extinction, Psychological; Fear; Fear conditioning; fear extinction; fiber photometry; Hippocampus; Innervation; Ligands; Mice; Microscopy; Neurons; Neurons - pathology; p75NTR; peri-adolescence; Photometry; polymorphism; Polymorphism, Single Nucleotide; Post traumatic stress disorder; prodomain; SorCS2; synapse elimination; Synapses; Synapses - pathology; Teenagers; ventral CA1
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.05.024

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. [Display omitted] •The BDNF Met prodomain eliminates spines in vCA1 neurons during peri-adolescence•The BDNF Met prodomain alters maturation of the fear extinction circuitry•BDNFMet/Met vCA1 neurons fail to adapt their activity during fear extinction trials The BDNF Val66Met prodomain is associated with reduced ability to extinguish fear memories. Giza et al. show that the BDNF Met prodomain eliminates spines in vCA1 neurons projecting to the PL, diminishing their capacity to adapt during extinction.