Extracellular zinc regulates contextual fear memory formation in male rats through MMP-BDNF-TrkB pathway in dorsal hippocampus and basolateral amygdala.

Large amount of zinc (100 µM even up to 300 µM) is released from the nerve terminals in response to high frequency neuronal stimulation in certain brain regions including hippocampus and amygdala. However, its precise pharmacological effect is poorly understood. Here, we investigated the role of extracellular zinc (endogenous zinc) and exogenous zinc in memory formation using contextual fear conditioning (CFC) model. Male Sprague Dawley rats were trained for fear conditioning followed by in vivo microdialysis for collection of microdialysate samples from CA1 and CA3 regions of hippocampus and basolateral amygdala (BLA). Extracellular zinc chelator CaEDTA, BDNF scavenger TrkB-Fc, exogenous 7,8-DHF and matrix metalloproteinases (MMP) inhibitor were infused into the CA1 and CA3 regions of hippocampus and BLA after CFC. Different doses of exogenous zinc hydroaspartate were administered intraperitoneally immediately after CFC. We found that CFC increased the level of extracellular zinc in the hippocampus and BLA. Infusing the CaEDTA, TrkB-Fc and MMP inhibitor into the CA1 and CA3 regions of hippocampus and BLA disrupted the fear memory formation. Furthermore, administration of TrKB agonist 7,8-DHF reversed the inhibitory effect of CaEDTA on fear memory formation, suggesting that extracellular zinc may regulate fear memory formation via the BDNF-TrKB pathway. We also found that high dose of exogenous zinc hydroaspartate supplementation increased extracellular zinc levels in brain and enhanced fear memory formation. Altogether, these findings indicate that extracellular zinc may participate in formation of contextual fear memory through MMP-BDNF-TrkB pathway in the hippocampus and BLA.