The entry of peripheral immune cells into brain border areas like the choroid plexus and meningesis established, but the mechanism regulating their infiltration and functional role is not fullyunderstood. Our study sheds light on the role of serotonin in the migration of these cells and theirinvolvement in the action of selective serotonin reuptake inhibitors (SSRIs). We found thatfluoxetine (FLX), which is known to boost available serotonin, led to a higher number of immunecells found in the brain (parenchyma and borders) of socially isolated mice. By employing spatial transcriptomics and single-cell genomics, we pinpointed the 5HT2C receptor as a key serotonergic receptor within the choroid plexus in the brain ventricles. We also show that the levels of this receptor increase in socially isolated mice. Chemogenetic activation of dorsal raphe serotonergic neurons or treatment with 5HT2C agonist similarly induced immune infiltration to the brain, mainly in the ventricular areas. However, blocking the 5-HT2C receptor in mice treated with SSRIs reduced immune cell entry and the antidepressant's positive effects. Furthermore, immune-deficient mice treated with FLX, showed no improvement in their behavioral scores, highlighting the potential role of immune cells in the SSRI action mechanism. Thus, we propose that serotonin serves as a gatekeeper for the brain, with the 5HT2C receptor as a crucial controller of the brain's immune cell composition. Modulating this gateway could have important implications for treating various conditions such as depression, autoimmune diseases, and neurodegenerative conditions.