Using the model of hypoxia-hypoglycemia (HH) in rat brain slices, we asked whether glutamate transmission is altered following a brief HH episode. The HH challenge was conducted by exposing slices to a glucose-free medium aerated with 95% N2-5% CO2, for approximately 4 min, and glutamate transmission in the hippocampal CA1 region was monitored at different post HH times. In slices examined </=8 h post HH, CA1 synaptic field potentials are comparable in amplitude to controls, but are less sensitive to experimental manipulations designed to attenuate intracellular Ca2+ signals, as compared with controls. Reducing calcium influx, by applying a nonspecific calcium channel blocker Co2+ or lowering external Ca2+, attenuated CA1 synaptic potentials much less in challenged slices than in controls. Buffering intracellular Ca2+ by bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid-AM (BAPTA-AM) attenuated CA1 synaptic potentials in control but not in slices post HH. Furthermore, minimally evoked excitatory postsynaptic currents displayed a lower failure rate in post-hypoxic CA1 neurons compared with controls. Based on these convergent observations, we suggest that evoked CA1 glutamate transmission is altered in the first several hours after brief hypoxia, likely resulting from alterations in intracellular Ca2+ homeostasis and/or Ca2+-dependent processes governing transmitter release.