Proposed mechanisms of effect of CO on presynaptic neurons and postsynaptic neurons on change to lactate as metabolic substrate. Ca2+ signaling has been proposed as the primary determiner of change from glucose to lactate metabolism in the brain. CO could block both NMDA R and VGCC allowing less Ca2+ to reach the cytoplasm. This would decrease the amount of glucose available for the mitochondrial TCA cycle in both the presynaptic and postsynaptic neurons. Physiologic cystosol Ca2+ also binds to aralar which allows an increase in malate transfer into the mitochondria and a change to the CiMASH pathway.