Zinc induced structural changes in the intrinsically disordered BDNF Met prodomain confer synaptic elimination.

Human brain derived neurotrophic factor (BDNF) encodes a protein product consisting of a C-terminal mature domain (mature BDNF) and an N-terminal prodomain, which is an intrinsically disordered protein. A common single nucleotide polymorphism in humans results in a methionine substitution for valine at position 66 of the prodomain, and is associated with memory deficits, depression and anxiety disorders. The BDNF Met66 prodomain, but not the Val66 prodomain, promotes rapid structural remodeling of hippocampal neurons' growth cones and dendritic spines by interacting directly with the SorCS2 receptor.

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

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.

The synaptic adhesion molecule SynCAM 1 contributes to cocaine effects on synapse structure and psychostimulant behavior.

Drugs of abuse have acute and persistent effects on synapse structure and addiction-related behaviors. Trans-synaptic interactions can control synapse development, and synaptic cell adhesion molecule (SynCAM) proteins (also named nectin-like molecules) are immunoglobulin adhesion proteins that span the synaptic cleft and induce excitatory synapses. Our studies now reveal that the loss of SynCAM 1 in knockout (KO) mice reduces excitatory synapse number in nucleus accumbens (NAc).