ETD

• fluoxetine
• hippocampus
• medial prefrontal cortex
• microglia
• plasticity
• serotonin

Serotonin (5-HT) is a key neurotransmitter involved in mood, anxiety, sleep, memory, nociception and development. In the CNS, serotonergic neurons from raphe nuclei project to cortical, limbic, midbrain and hindbrain regions. Using a Tph2GFP mouse model, our lab previously showed that fluctuations in brain 5-HT induce reversible rearrangements of the serotonergic system. Depletion via Tph2 inactivation caused marked hyperinnervation in hippocampus and prefrontal cortex, rescued by chronic 5-hydroxytryptophan. Conversely, chronic fluoxetine (flx), a widely used SSRI, which likely induces fluctuations of 5-HT within a peri-physiological range induced a reversible reduction of serotonergic innervation, suggesting homeostatic plasticity.
Microglia, the immune cells of the CNS, also regulate synaptic plasticity and express the 5-HT2B receptor. We hypothesized that flx-induced serotonergic remodeling might be mediated by microglia via 5-HT2B. To test this hypothesis, four cohorts of Tph2GFP+/- mice were treated for 28 days with vehicle, flx, flx/RS127445 (5-HT2B antagonist) or BW723C86 (5-HT2B agonist). In the Novelty-Suppressed Feeding Test, both flx and BW723C86 reduced depressive-like behavior, whereas flx/RS127445 did not. Analysis of serotonergic innervation revealed reductions in hippocampus and medial prefrontal cortex in flx- and BW723C86-treated mice, but not in flx/RS127445, strongly suggesting that microglial 5-HT2B receptors mediate these effects.