Serotonin Plays a Role in Maintaining the Differentiated Phenotype of Central Serotonergic Neurons by 5-HT1A Receptor

Serotonin (5-hydroxytryptamine, 5-HT) and its receptors have been extensively studied in the context of modulation of animal behaviors. However, much less is known about their functions in the development and maintenance of 5-HT neurotransmitter phenotype. Here, we report that in the rostral raphe nuclei of mice lacking tryptophan hydroxylase 2 (Tph2), expression of transcription factors Pet1, Gata3 and 5-HT1A receptor (5-HT1AR) is significantly reduced in postnatal 5-HT neurons relative to the control mice. Importantly, the spatiotemporal-restricted decreased expression of Pet1 is recapitulated in the raphe nuclei of 5-HT1AR -/- mice. Using an explant culture system, we show that reduction of Pet1 and 5-HT1AR is rescued in Tph2-/- brainstem by 5-HT. In contrast, 5-HT fails to rescue reduced expression of Pet1 in 5-HT1AR -/- brainstem explant culture. Moreover, the treatment of 5-HT1AR antagonist blocks the induction of Pet1 expression by 5-HT in Tph2 null hindbrain. These results suggest that 5-HT, 5-HT1AR and Pet1 form an autoregulatory feedback loop to maintain the differentiated phenotype of 5-HT neurons, and 5-HT1AR is a key receptor linking 5-HT signaling and Pet1 expression. The identification of a 5-HT1AR-dependent autoregulatory mechanism required for maintaining 5-HT homeostasis may be relevant to understanding the etiology of certain psychiatric and developmental disorders