Abstract
BackgroundDespite the importance of 5-HT1A as a major target for the action of several anxiolytics/antidepressant drugs, little is known about its regulation in central serotonin (5-hydroxytryptamine, 5-HT) neurons.ResultsWe report that expression of 5-HT1A and the transcription factor Pet1 was impaired in the rostral raphe nuclei of mice lacking tryptophan hydroxylase 2 (Tph2) after birth. The downregulation of Pet1 was recapitulated in 5-Ht1a -/- mice. Using an explant culture system, we show that reduction of Pet1 and 5-HT1A was rescued in Tph2 -/- brainstem by exogenous 5-HT. In contrast, 5-HT failed to rescue reduced expression of Pet1 in 5-Ht1a -/- brainstem explant culture.ConclusionsThese results suggest a causal relationship between 5-HT1A and Pet1, and reveal a potential mechanism by which 5-HT1A-Pet1 autoregulatory loop is maintained by 5-HT in a spatiotemporal-specific manner during postnatal development. Our results are relevant to understanding the pathophysiology of certain psychiatric and developmental disorders.
Highlights
Despite the importance of 5-HT1A as a major target for the action of several anxiolytics/antidepressant drugs, little is known about its regulation in central serotonin (5-hydroxytryptamine, 5-HT) neurons
Normal generation and migration of presumptive central serotonergic neurons in tryptophan hydroxylase 2 (Tph2)-/- mice To generate Tph2-/- mice, two loxP sites were inserted to flank the exon 5 that encodes eukaryotic tryptophan hydroxylase domain essential for 5-HT synthesis (Figure 1A)
Actb cre mice were mated with Tph2f/+ mice to inactivate Tph2 in the germline, and Tph2+/- and Tph2-/- mice were born at the expected mendelian ratio
Summary
Normal generation and migration of presumptive central serotonergic neurons in Tph2-/- mice To generate Tph2-/- mice, two loxP sites were inserted to flank the exon 5 that encodes eukaryotic tryptophan hydroxylase domain essential for 5-HT synthesis (Figure 1A). Our results are different from several recent studies which showed that expression of 5-Ht1a autoreceptor in dorsal raphe nuclei was slightly increased in Tph2-/- mice [27] or remained the same [37]. An altered 5-Ht1a/Pet expression and regulation may impact other 5-HT autoreceptors and thereby contribute to the development of mood disorders (e.g. major depressive disorder, aggression and anxiety) [21,42,46,47,49,50] In this context, the identification of a 5-HT-dependent 5-Ht1a/Pet autoregulatory feedback loop (Figure 5C) required for maintaining appropriate 5-HT signaling and homeostasis in postnatal raphe nuclei is of important clinical implications for designing target-specific therapeutic intervention of these disorders
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