The role of serotonin in respiratory function and dysfunction

Abstract

Serotonin (5-HT) is a neuromodulator-transmitter influencing global brain function. Past and present findings illustrate a prominent role for 5-HT in the modulation of ponto-medullary autonomic circuits. 5-HT is also involved in the control of neurotrophic processes during pre- and postnatal development of neural circuits. The functional implications of 5-HT are particularly illustrated in the alterations to the serotonergic system, as seen in a wide range of neurological disorders. This article reviews the role of 5-HT in the development and control of respiratory networks in the ponto-medullary brainstem. The review further examines the role of 5-HT in breathing disorders occurring at different stages of life, in particular, the neonatal neurodevelopmental diseases such as Rett, sudden infant death and Prader-Willi syndromes, adult diseases such as sleep apnoea and mental illness linked to neurodegeneration.

Fig. 1. Schematic illustration of 5-HT biosynthesis and neurotransmission

L-Tryptophan (L-Trp) is transformed in 5-hydroxytryptophan (5-HTP) by the enzyme Tryptophan hydroxylase (Tph) and subsequently into serotonin (5-HT) by the enzyme Aromatic L-amino acid decarboxylase (Aadc). In normal conditions, the rate-limiting step of the 5-HT biosynthesis is Tph and not Aadc. After 5-HT release re-uptake is mediated via the serotonin transporter (SERT) and is degraded in 5-hydroxy-indol acetic acid (5-HIAA) by the enzyme monoamine oxydase A (MAOA). Common pharmacological tools used to alter the 5-HT biosynthesis such as p-chlorophenylalanine (pcpa) which blocks 5-HT synthesis, MAOA inhibitors (I-MAOA) which block the degradation and the antidepressant Fluoxetine which blocks 5-HT re-uptake are also illustrated.

Fig. 2. Distribution and connectivity of serotonin neurons in the brainstem

Neurons synthesizing 5-HT are found in distinct cell groups called as the raphe in the brainstem. These cells form a column along the midline extending from the caudal medulla to the midbrain. The raphé neurons project to virtually all regions of the neuraxis. The hashed line is intended to elucidate the columnar structure of the raphe system along the midline. The red regions indicate the respiratory columns. Rob: raphe obscurus; RMg: raphe magnus; RPa: raphe pallidus; PnR: pontine raphe nuclei; DRc: caudal dorsal raphe; DR: dorsal raphe; VRC: ventral respiratory column; NTS: nucleus tractus solitari; PRC: pontine respiratory column; KF: Kölliker-Fuse; XII: hypoglossal motor nuclei; PAG: periaqueductal gray.

Fig. 3. 5-HT modulation of neonatal respiratory activity

A) Traces showing in vitro phrenic bursts recorded from en bloc preparations of neonatal mice and changes evoked following bath application of 25μM 5-HT (horizontal bar). Note that 5-HT application induced complex effects characterized by an increase in phrenic burst frequency (due to activation of medullary 5-HT_1AR), a tonic discharge of motoneurons (due to activation of spinal 5-HT_2AR) and a reduction in phrenic burst amplitude (due to a possible presynaptic activation of spinal 5-HT_1BR). Scale bar: 1 min (see Bou-Flores et al., 2000). B) 5-HT_2AR activation depolarizes phrenic motoneurons. Intracellular recording of a phrenic motoneuron before (B1) and after 5-HT application (B2). 5-HT induced a 20mV depolarization and a tonic firing of the motoneuron (time scale: 1 s; spikes truncated). B3: Immunohistochemistry reveals that neonatal phrenic motoneurons (retrogradely labelled with rhodamine) widely express 5-HT_2AR (white dots). Calibration bar: 20 μm. (see also Bras et al., 2008) C) 5-HT neurons synaptically coupled with respiratory neurons. Schematic drawing illustrates medullary neurons that project to phrenic motoneurons in neonatal mice after rabies virus (RV) inoculated in the diaphragm at P1. After RV inoculation in the diaphragm, RV progressively infected neurons controlling phrenic motoneuronal output. Thirty hours after inoculation phrenic motoneurons were labeled. After 36 hours neurons in the VRC revealed labeling and after 42 hours infected neurons were observed in histochemically identified 5-HT neurons of the raphe nuclei obscurus (1–2) and pallidus (3–4). These experiments illustrate the synaptic connectivity of raphe 5-HT neurons with phrenic premotor neurons in the VRC. Calibration bars: 100 μm. (also see Zanella et al., 2008)

Fig. 4. Genetic determination and genesis of 5-HT neurons

During the early embryogenesis 5-HT neurons are generated from ventricular zone precursors controlled by fibroblast growth factors 4 and 8 (Fgf4 and Fgf8) and sonic hedgehog (Shh). In post-mitotic neurons, a complex network of genes such as Pet1, Lmx1b, Nkx2.2, Mash1, Gata2, Gata3, and Phox2b will determine the important proteins for 5-HT biosynthesis and neurotransmission such as Tph, Aadc, SERT. (for details see Fig. 1).