Medullary serotonin neurons and central CO2 chemoreception

Abstract

Serotonergic (5-HT) neurons are putative central respiratory chemoreceptors, aiding in the brain's ability to detect arterial changes in PCO2 and implement appropriate ventilatory responses to maintain blood homeostasis. These neurons are in close proximity to large medullary arteries and are intrinsically chemosensitive in vitro, characteristics expected for chemoreceptors. 5-HT neurons of the medullary raphé are stimulated by hypercapnia in vivo, and their disruption results in a blunted hypercapnic ventilatory response. More recently, data collected from transgenic and knockout mice have provided further insight into the role of 5-HT in chemosensitivity. This review summarizes current evidence in support of the hypothesis that 5-HT neurons are central chemoreceptors, and addresses arguments made against this role. We also briefly explore the relationship between the medullary raphé and another chemoreceptive site, the retrotrapezoid nucleus, and discuss how they may interact during hypercapnia to produce a robust ventilatory response.

Figure 1

Serotonergic neurons have properties expected of central respiratory chemoreceptors. A) Confocal image of the ventral surface of the medulla. 5-HT neurons (green and yellow) are concentrated near the basilar artery and its main branches (red). Reproduced with permission from Bradley et al. (2002). B) Patch-clamp recording of a medullary raphé 5-HT neuron at a baseline pH of 7.4 (control) and exposed to pH 7.2. Acidosis causes an increase in firing rate. Reproduced with permission from Wang et al., (2002).

Figure 2

Raphé neurons are intrinsically sensitive, responding to hypercapnic acidosis after acute dissociation. Shown is a 13 day old 5-HT neuron acutely dissociated from a genetically modified mouse that expresses yellow fluorescent protein (YFP) in 5-HT neurons (Scott et al., 2005). Images on the left were taken using differential interference contrast (DIC) and fluorescence microscopy (YFP). The recording was made 3 days after acute dissociation, which is long enough to allow synaptic terminals and glial processes to die off, but not long enough for new synaptic connections to be made or for regrowth of glial processes. This approach ensures that the response to pH is intrinsic to the recorded neuron. Shown on the right is the firing rate response to hypercapnic acidosis. The magnitude of the response was typical for raphé neurons of the same age recorded in slices and in culture.

Figure 3

Raphé neurons are chemosensitive in unanesthetized animals. A) In vivo recordings of individual 5-HT raphé neurons in cats in response to increasing inhaled CO₂. Some neurons display a non-linear response to CO₂, requiring a threshold level of CO₂ to be reached before increasing their firing rate. B) There is a close correlation between the firing rate of some raphé neurons recorded in vivo and the increase in minute ventilation in response to inhaled CO₂. Adapted with permission from Veasey et al. (1995).

Figure 4

A) Development of the hypercapnic ventilatory response in Sprague-Dawley rats in vivo. Note that there is very little response to 7% CO₂ (expressed as a percentage of eucapnia) during the first two weeks post-natal, and increases significantly after around P12–P14. Adapted with permission from Davis et al. (2006). B) Sprague-Dawley rat raphé neurons recorded in slices and in tissue culture do not develop significant chemosensitivity until they are older than P12. Modified with permission from Wang et al. (1999).

Figure 5

A) Midbrain 5-HT neurons from wild type mice have no response to a decrease in pH from 7.5 to 7.3, and a two-fold response to a decrease in pH from 7.3 to 6.9. In contrast, midbrain 5-HT neurons from mice with genetic deletion of TASK-1 and/or TASK-3 do not respond to changes in pH between 6.9 and 7.5. Adapted with permission from Mulkey et al. (2007b). B) Comparison of responses of mouse midbrain raphé neurons reported by Mulkey et al. (2007b) and values previously reported in rat medullary raphé neurons (Wang et al., 2002). The small response for wild-type mice is re-plotted from part A, and is contrasted with the large response in rats.