The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism is a common genetic variant associated with neuropsychiatric disorders. This substitution of valine for a methionine in the BDNF prodomain (pBDNF Met) induces structural and functional impairments in the central nervous system (CNS), including growth cone retraction, altered dendritic morphology, circuitry remodelling, functional deficits measured by calcium fiber photometry, and behavioral alterations. However, the cellular mechanisms driving these effects remain poorly understood. Our group recently showed that pBDNF Met interacts with zinc (Zn²⁺) to form large multimers which are required for pBDNF Met effects. As both Zn²⁺ and pBDNF Met coexist in the secretory pathway, we hypothesize that this interaction alters intracellular trafficking, contributing to the neuronal defects. Using an in vitro synchronization system in cultured hippocampal neurons, we observed that pBDNF Met impairs vesicular trafficking in neuronal processes. Interestingly, preliminary findings suggest that lithium can prevent Zn²⁺-induced pBDNF Met multimerization. Therefore, we are currently testing whether lithium can also rescue trafficking defects, dendritic alterations, and fear extinction impairments induced by pBDNF Met. Our results indicate that lithium restores dendritic complexity, and ongoing experiments aim to determine whether it also prevent intracellular trafficking defects.