NEUROBIOLOGY How CO₂ Bidirectionally Influences Neural Excitability

In addition to the effects changes in CO₂ concentrations have on respiration and vascular tone, CO₂ also influences neural excitability. Decreasing CO₂ can induce seizures, whereas increasing CO₂ produces sedation. Dulla et al. show that, in hippocampal slices, hypercapnia (10 or 20% CO₂) produced a decrease in field excitatory postsynaptic potentials (fEPSPs) or excitatory postsynaptic currents (EPSCs), whereas hypocapnia (2% CO₂) produced an increase in fEPSPs or EPSCs. This change in synaptic activity was not affected by addition of pharmacological blockers of the ionotropic -aminobutyric acid type A (GABA_A) receptors. Two-photon imaging showed that intracellular pH decreased when CO₂ was elevated and increased when CO₂ was decreased. However, there was stronger correlation between the effects on fEPSPs of changes in extracellular pH than with changes in intracellular pH. Extracellular adenosine concentrations were altered by changes in CO₂, with hypercapnia causing an increase in extracellular adenosine and hypocapnia causing a decrease. The ratio of adenosine to adenosine triphosphate (ATP) is regulated by the activity of ecto-ATPase, which is a pH-sensitive enzyme. Blockade of both ATP receptors and inhibition of ecto-ATPase (ecto-adenosine triphosphatase) completely abolished the excitatory effects of hypocapnia. Thus, hypocapnia appears to increase pH, which decreases the activity of the ecto-ATPase, thereby increasing the excitatory effects of ATP, while decreasing the inhibitory effects of adenosine. Thus, changes in CO₂ appear to shift the balance of ATP and adenosine such that the inhibitory effect of adenosine predominates at high CO₂ and the excitatory effects of ATP predominate at low CO₂. In a model of epilepsy, hypercapnia decreased the synaptic burst activity and this was abolished by the addition of an inhibitor of adenosine A1 receptors. This provides a mechanism for hyperventilation-induced seizures in humans.

C. G. Dulla, P. Dobelis, T. Pearson, B. G. Frenguelli, K. J. Staley, S. A. Masino, Adenosine and ATP link P_CO2 to cortical excitability via pH. Neuron 48, 1011-1023 (2005). [PubMed]