Adenosine and adenosine triphosphate link PCO2 to cortical excitability via pH

Changes in systemic CO2 levels trigger a gamut of neurological responses. We examined the effects of hypercapnia and hypocapnia on neuronal excitability, pH, and extracellular adenosine concentration in the hippocampal slice preparation from male Sprague Dawley rats age 4--8 weeks. We used extracellular field recording of excitatory post-synaptic potentials from CA1, network field bursting in area CA3, enzymatic adenosine sensor measurements, and 2-photon intracellular pH measurement to measure these parameters. Hypercapnia ( PCO2 10%, pH = 7.0 or PCO2 20%, pH = 6.7) caused adenosine release and adenosine and ATP-dependent inhibition of synaptic transmission in area CA1. This was due to decreased extracellular pH as neither isohydric hypercapnia ( PCO2 10%, pH = 7.3) nor propionic acid (intracellular acidification alone) caused adenosine release or altered synaptic transmission. Hypocapnia ( PCO2 2%, pH = 7.7) decreased extracellular adenosine concentrations and increased neuronal excitability via ecto-ATPase, adenosine A1-receptors and ATP P2-receptors. Hypercapnia caused adenosine-dependent attenuation of epileptiform activity in area CA3. Hypocapnia increased the frequency of epileptiform activity via adenosine A1-receptors and ATP P2-receptors. Based on these studies, adenosine and ATP contribute to CO2-induced changes in excitability and represents an important new transduction mechanism for the neurological effects of CO2 in vivo.