Neuroenergetic models of synaptic transmission predicted that energy demand is highest for action potentials (APs) and postsynaptic ion fluxes, whereas the presynaptic contribution is rather small. Here, we addressed the question of energy consumption at Schaffer-collateral synapses. We monitored stimulus-induced changes in extracellular potassium, sodium, and calcium concentration while recording partial oxygen pressure (pO(2)) and NAD(P)H fluorescence. Blockade of postsynaptic receptors reduced ion fluxes as well as pO(2) and NAD(P)H transients by ∼50%. Additional blockade of transmitter release further reduced Na(+), K(+), and pO(2) transients by ∼30% without altering presynaptic APs, indicating considerable contribution of Ca(2+)-removal, transmitter and vesicle turnover to energy consumption.