Sequential activation of the 5-HT1(A) serotonin receptor and TrkB induces the serotonergic neuronal phenotype

Serotonin (5-HT) is an important factor controlling survival, differentiati on, and plasticity of neurons in serotonergic target regions of the brain a nd has been implicated in major psychiatric and autonomic disorders. Relati vely little is known, however, of factors controlling differentiation and p lasticity of developing and adult 5-HT neurons. We show now that 5-HT, the 5-HT1(A) receptor, brain-derived neurotrophic factor (BDNF), and its recept or, trkB, form an auto/paracrine loop for the regulation of the serotonergi c phenotype. Serotonin applied to cultures from E14 rat raphe increased num bers of neurons expressing serotonergic markers in a dose-dependent manner. Agonists of the 5-HT1(A) receptor, BP-554 and 8-OH-DPAT, but not agonists of the 5-HT1(B) and 5-HT1(D) receptors, mimicked this effect, while the spe cific 5-HT1(A) antagonist, WAY-100635, inhibited it. Serotonin also increas ed BDNF mRNA and protein in embryonic raphe cultures. Induction of serotone rgic markers by serotonin was suppressed by a trkB-IgG fusion protein but n ot by trkC-IgG. Taken together, our data indicate that serotonin acts on 5- HT1(A) autoreceptors, causing up-regulation of BDNF, which activates trkB t o promote serotonergic phenotype-specific markers.