Moderate Changes in CO2 Modulate the Firing of Neurons in the VTA and Substantia Nigra.

Emily Hill,Nicholas Dale,Mark J Wall

doi:10.1016/j.isci.2020.101343

Abstract

SummaryThe substantia nigra (SN) and ventral tegmental area (VTA) are vital for the control of movement, goal-directed behavior, and encoding reward. Here we show that the firing of specific neuronal subtypes in these nuclei can be modulated by physiological changes in the partial pressure of carbon dioxide (PCO2). The resting conductance of substantia nigra dopaminergic neurons in young animals (postnatal days 7–10) and GABAergic neurons in the VTA is modulated by changes in the level of CO2. We provide several lines of evidence that this CO2-sensitive conductance results from connexin 26 (Cx26) hemichannel expression. Since the levels of PCO2 in the blood will vary depending on physiological activity and pathology, this suggests that changes in PCO2 could potentially modulate motor activity, reward behavior, and wakefulness.

Highlights

Carbon dioxide (CO2) is a waste product of cellular metabolism with its concentration in blood a major regulator of breathing
We show that the firing of specific neuronal subtypes in these nuclei can be modulated by physiological changes in the partial pressure of carbon dioxide (PCO2)
The resting conductance of substantia nigra dopaminergic neurons in young animals and GABAergic neurons in the ventral tegmental area (VTA) is modulated by changes in the level of CO2

Summary

Introduction

Carbon dioxide (CO2) is a waste product of cellular metabolism with its concentration in blood a major regulator of breathing. PH sensing via ventral medullary glial cells may contribute to the CO2-dependent regulation of breathing (Gourine et al, 2010; Turovsky et al, 2016). The midpoint for the binding is $40 mm Hg, which, as indicated above, is the resting level in human blood, and small changes in PCO2 will shift the open probability of Cx26 hemichannels. Pharmacological evidence suggests that Cx26 contributes to the CO2-dependent regulation of breathing (Gourine et al, 2005; Huckstepp et al, 2010b; Wenker et al, 2012), and this has recently gained support from genetic evidence that links binding of CO2 to Cx26 to the adaptive change in breathing (van de Wiel et al, 2020)

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