Editors' ChoiceNeurobiology

How CO2 Bidirectionally Influences Neural Excitability

Science's STKE  03 Jan 2006:
Vol. 2006, Issue 316, pp. tw463
DOI: 10.1126/stke.3162006tw463

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 γ-aminobutyric acid type A (GABAA) 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 PCO2 to cortical excitability via pH. Neuron 48, 1011-1023 (2005). [PubMed]