Microglial Expression of Serotonin Receptors Reveals Parallel Regulation of 5-HT2b and BDNF in the Rat Hippocampus

Growing evidence suggests that psychiatric disorders are characterized by a prolonged inflammatory state, which may influence the efficacy of compounds targeting serotonin. Serotonin is a key signaling molecule in neuroplasticity of the adult hippocampus and involved in antidepressant action. Recent in vitro studies indicate the neurotransmitter may also facilitate the response to inflammation and potentially modulate microglial function towards neuroprotection. Using Tph2^-/- rats depleted of brain serotonin, we examined microglial expression of various serotonin receptors (5-HTRs) in vivo in both the hippocampus and prefrontal cortex and assessed mRNA levels of cytokines and brain-derived neurotrophic factor (BDNF). We observed age-dependent and region-specific gene expression of 5-HTRs on sorted microglia, paralleling changes in BDNF signaling, especially with 5-HT2b. Notably, both 5-HT2b and BDNF expression in the hippocampus was significantly upregulated in the absence of brain serotonin. Our data indicate distinct roles of 5-HTR subtypes in early network formation (5-HT1b, 5-HT5b) and in the response to endogenous changes (5-HT2b, 5-HT5a). Understanding serotonin-microglia interplay could offer therapeutic insights into the maintenance of mood via brain-immune cell interactions.