The serotonergic system and the control of breathing during development

Abstract

Serotonin (5-hydroxytryptamine 5-HT) was first discovered in the late 1940's as an endogenous bioactive amine capable of inducing vasoconstriction, and in the mid-1950's was found in the brain. It was in these early years that some of the first demonstrations were made regarding a role for brain 5-HT in neurological function and behavior, including data implicating reduced brain levels of 5-HT in clinical depression. Since that time, advances in molecular biology and physiological approaches in basic science research have intensely focused on 5-HT in the brain, and the many facets of its role during embryonic development, post-natal maturation, and neural function in adulthood continues to be established. This review focuses on what is known about the developmental roles for the 5-HT system, which we define as the neurons producing 5-HT along with pre-and post-synaptic receptors, in a vital homeostatic motor behavior - the control of breathing. We will cover what is known about the embryonic origins and fate specification of 5-HT neurons, and how the 5-HT system influences pre- and post-natal maturation of the ventilatory control system. In addition, we will focus on the role of the 5-HT system in specific respiratory behaviors during fetal, neonatal and postnatal development, and the relevance of dysfunction in this system in respiratory-related human pathologies including Sudden Infant Death Syndrome (SIDS).

Keywords: Control of breathing; Development; Serotonin.

Figure 1.. Development and function of the 5-HT system in the prenatal and early postnatal periods.

5-HT progenitor cells require induction by Sonic hedgehog (Shh) to drive expression of transcription factors Nkx2.2 and Foxa2, the latter represses Phox2b to dictate a 5-HT neuron cell fate. Along with expression of Ascl1 around embryonic day (E)10, these transcription factors then drive coordinated expression of Gata2, Gata3, and Insm1 to ultimately drive gene expression for Lmx1b and Pet1 beginning around E11.5. The presence of these transcription factors drive coordinate expression of several post-mitotic precursor genes that derive a 5-HT neuronal “fingerprint”, including tryptophan hydroxylase 2 (Tph2), the serotonin transporter (Slc6a4; 5-HTT), dopa decarboxylase (Ddc), OCT3 (Slc22a3), VMAT2 (Slc18a2), monoamine oxidase B (MAOB), and 5-HT_1A (Hrt1a) and 5-HT_1B (Hrt1b) receptors by E14.5. Data from a variety of animal models of central 5-HT deficiency suggest that 5-HT is critical for maintaining respiratory frequency (f) starting around E18 until the end of the first postnatal (P) week. There are two windows of postnatal development (P0–5 and P12–15) in which 5-HT is particularly important for maintaining breathing frequency (f) and overall ventilation (V_E), as well as reducing apneas. Other functions include promotion of gasping during severely hypoxic conditions from birth until around P9. 5-HT_2A receptors appears to be most important for these functions, although 5-HT₁ receptors may have a role before birth. Rodents with 5-HT system dysfunction across the neonatal period display age-dependent respiratory phenotypes that reflect these important functions, but have two periods of vulnerability at P0–2 and P12–15 (i.e. “critical periods”; indicated by black bars with skull and crossbones). Of note, the critical period beginning at P12 coincides with a decrease in expression of a number of vital 5-HT system components (Tph2, 5-HT receptors).