The ischemia-induced synaptic potentiation (ISP) during and/or after brain ischemia has been suggested to be one of the crucial factors responsible for irreversible neuronal damage of hippo-campal CA1 pyramidal neurons. However, the presynaptic modulation mechanism that leads to neuronal damage during and/or after ischemia was still unknown. By combining electrophysiological methods and infra-red differential interference contrast (IR-DIC) imaging procedures, we showed for the first time that ISP is the result of extraordinary presynaptic depolarization in association with the suppression of 4-amino-pyridine (4-AP) sensitive K channels at the presynaptic sites. Furthermore, we also showed that the 4-AP sensitive presynaptic K channels played a crucial role in inducing neuronal damage at a very acute phase of ischemia-induced neuronal damage and would be a therapeutic target against the neuronal damage after brain ischemia.