In conclusion, we unravel AMPAR surface diffusion as a potential novel therapeutic target for early intervention in HD and propose a new therapeutic strategy for HD using the antidepressant tianeptine, which improves hippocampal synaptic and memory deficits as well as anxiety/depression-like behavior in HD mice possibly through the modulation of BDNF signaling and AMPAR surface diffusion. Here, BDNF is linked to major depressive disorder.