Hypoxia leads to a rapid increase in vesicular release of glutamate. In addition, hypoxic glutamate release might be caused by reversed operation of neuronal glutamate transporters. An increase in extracellular glutamate concentration might be an important factor in generating anoxic depolarizations (AD) and subsequent neuronal damage. To study the AD and the vesicular release in hippocampal slices from CD1 wild-type mice and mice in which the neuronal glutamate transporter excitatory amino acid carrier 1 (EAAC1) had been knocked out, the authors performed recordings of field potentials and patch clamp recordings of CA1 pyramidal cells. Latency to anoxic depolarizations was enhanced in EAAC1^−/− mice, whereas the hypoxia-induced increase in miniature excitatory postsynaptic current frequency occurred with similarly short latencies and to a similar extent in control and mutated animals. Additional block of glial glutamate uptake with TBOA (dl-threo-β-benzyloxyaspartate), a nontransportable and potent inhibitor, dramatically reduced the latency to onset of AD and abolished the difference between wild-type mice and EAAC1^−/− mice. The authors conclude that the neuronal glutamate transporter greatly influences the latency to generation of AD. Because ADs are not prevented in EAAC1-deficient mice, vesicular release mechanisms also seem to be involved. They become prominent when glial glutamate transport is blocked.