Serotonin Neurons & pH Homeostasis

Serotonin Neurons & pH Homeostasis

Medullary serotonergic neurons are sensors for CO₂ and pH

Membrane potential of an acidosis-stimulated neuron Blood pH is tightly controlled, because even small changes in pH can be fatal. One of the major mechanisms for this pH regulation is via regulation of carbon dioxide levels, since CO₂ and pH are in equilibrium through the chemical reaction H₂O + CO₂ » H⁺ + HCO₃^-.

Firing rate of a stimulated neuron

To regulate CO₂, there are neurons in the brain called central respiratory chemoreceptors that monitor CO₂ and alter the rate and depth of lung ventilation. Recently, we have shown that neurons in the medulla that produce serotonin (serotonergic neurons) have properties expected of central respiratory chemoreceptors. For example, they are strongly stimulated by an increase in CO₂ via the resulting decrease in pH (Figure 1 and 2).

Serotonergic neurons in the medulla are also closely associated with large branches of the basilar artery (Figure 3). This is an ideal location for central respiratory chemoreceptors, because the CO₂ of blood in these large arteries would not yet have been altered by tissue metabolism, so that the CO₂ of blood in these large arteries would more closely reflect the effectiveness of lung ventilation than the CO₂ of blood in capillaries or veins.

Confocal image of raphe pallidus
There is now a variety of data from other laboratories using in vivo experiments that support a role of medullary serotonergic neurons as central respiratory chemoreceptors.

Our current work is aimed at studying the properties of serotonergic neurons to understand how they carry out their function as central chemoreceptors. To define these properties and their mechanisms we are using a combination of patch clamp recordings from brain slices and tissue culture, multielectrode array recordings, intracellular pH imaging, immunohistochemistry, and molecular biology. Our major goals are to define the mechanisms of pH chemosensitivity and how serotonergic neurons modulate downstream neurons in response to acidosis.

Midbrain serotonergic neurons are also sensors for CO₂ and pH Firing rate of a midbrain raphe neuron

Our initial work focused on the role of medullary serotonergic neurons in respiratory control. However, serotonergic neurons in the midbrain have many properties in common with those in the medulla. Therefore, we examined the effect of CO₂ / pH on midbrain serotonergic neurons. We found that midbrain neurons are also highly sensitive to changes CO₂ and pH (Figure 4).

Confocal image of midbrain raphe

Midbrain serotonergic neurons are also closely associated with large branches of the basilar artery that penetrate the midline of the midbrain (Figure 5). Thus, midbrain serotonergic neurons also appear to be central chemoreceptors. However, they are not involved in control of breathing. Instead, midbrain serotonergic neurons project to the forebrain and are involved in arousal, limbic function and cerebrovascular control. We have proposed that these chemosensitive midbrain serotonergic neurons mediate the arousal, anxiety and changes in cerebral blood flow that are known to occur when blood CO₂ rises.

Do serotonergic neurons throughout the brainstem share a role as CO₂ / pH sensors? Blind men and the elephant

Since the majority (>90%) of serotonergic neurons in the medulla are stimulated by acidosis, some of these neurons must project to nonrespiratory nuclei. If this is the case, then what do these neurons do? How does this relate to the fact that the majority of serotonergic neurons in the midbrain are also chemosensitive? Many of the neural systems influenced by serotonergic neurons are also sensitive to changes in blood CO₂, so it is reasonable to suppose that serotonergic neurons mediate nonrespiratory effects of increased CO₂. Our hypothesis is that chemosensitive serotonergic neurons induce a variety of downstream effects aimed at restoring pH homeostasis in response to a CO₂ challenge, including increased ventilation, changes in autonomic output, arousal, anxiety and altered cerebrovascular flow.

Serotonin and human disease

There are many human diseases that are linked to serotonin. These include sleep apnea, panic disorder, epilepsy, migraine, and SIDS. Interestingly, each of these disorders are also affected by CO₂, or related to defects in CO₂ chemoreception. Perhaps the most exciting link is with SIDS (sudden infant death syndrome). Scientists at Harvard and Dartmouth led by Hannah Kinney, have shown that there are abnormalities in the serotonin system of infants who have died of SIDS. A leading hypothesis for the pathophysiology of SIDS has been that there are maturational defects of the brainstem in these infants that lead to abnormalities of CO₂ chemoreception, breathing and arousal. This is interesting, because if serotonergic neurons are central chemoreceptor neurons that induce arousal and increased breathing, a defect in them would be expected to cause precisely the problem thought to occur in SIDS victims, i.e., blunting of the reflex hyperventilation and arousal that occurs in response to hypercapnia during sleep. We have initiated a collaboration with these scientists to better understand the mechanisms by which a defect in serotonergic neurons might lead to SIDS.

The overall goal of our lab is to determine the mechanisms by which serotonergic neurons sense changes in CO₂, and how their downstream effects contribute to control of pH. Defining the mechanisms of central respiratory chemoreception may lead to specific treatments for diseases in which respiratory chemoreception is abnormal and provide a better understanding of how CO₂ and pH affect CNS function.

For more detailed information about the work described here, please see our published papers and reviews in our list of publications.