Physiological Changes in CO <sub>2</sub> Modulate the Firing of Neurons in the VTA and Substantia Nigra

Abstract

The substantia nigra (SN) and ventral tegmental area (VTA) are vital for control of movement, goal-directed behaviour and encoding reward respectively. Surprisingly we find that firing of neurons in these nuclei can be modulated by physiological changes in PCO2. CO2 is a waste product of cellular metabolism, and its levels in blood are a key regulator of breathing. In humans, PCO2 in blood is normally ~40 mmHg but can be increased in conditions such as COPD and sleep apnoea and decreased by hyperventilation. Blood PCO2 can be detected by hemichannels of Connexin 26 (Cx26), which are expressed by glial cells on the medullary surface and play a key role in the control of breathing. Hemichannel-mediated CO2 -sensing has not been described in other brain regions. However dopaminergic neurons (DNs) in the SN of young rodents (P7-10) express mRNA for Cx26 and Cx30 which are CO2-sensitive. By P17-21 the DNs express only CO2-insensitive connexins. Here we show that the DNs (at P7-10) possess functional Cx26 hemichannels that allow physiological variations of CO2 to modulate their excitability. As predicted from their connexin mRNA profile, these neurons lose their CO2 sensitivity at later ages. Unexpectedly, we also found a nearby population of GABAergic neurons in the VTA which possess CO2 sensitive hemichannels of Cx26. These neurons retain their CO2 sensitivity throughout postnatal development. Our findings reveal an unexpected role for CO2 in regulating the activity of these key brain regions and demonstrates a mechanism by which autonomic state can alter complex movement-related and goal-directed behaviours.