CHARACTERIZATION OF THE ANOXIA-INDUCED LONG-TERM SYNAPTIC POTENTIATION IN AREA CA1 OF THE RAT HIPPOCAMPUS

1 The purpose of the present study was to characterize the mechanisms underlying the anoxia-induced long-term potentiation (LTP) of glutamat ergic synaptic transmission in the CA1 region of rat hippocampus by us e of intracellular recordings in vitro. 2 In response to superfusion o f an anoxic medium equilibrated with 95% N-2-5% CO2, the initial slope (measured within 3 ms from the onset of the synaptic response) of the excitatory postsynaptic potential (e.p.s.p.) generated in the hippoca mpal CA1 neurones by stimulation of Schaffer collateral-commissural af ferent pathway was significantly decreased by 91.3+/-4.9% (n=10) withi n 10 min of the anoxic episode. The reduction of the initial slope of the e.p.s.p. was accompanied by a transient membrane hyperpolarization followed by a sustained depolarization (10.8+/-1.7 mV, n=10), along w ith a reduction in membrane input resistance (69.3+/-4.8% of control, n=10). On return to reoxygenated medium, the e.p.s.p. slope returned t o the control value within 8-10 min and was subsequently and progessiv ely potentiated to reach a plateau (195.6+/-14.7% of control, n=10) 15 -20 min after return to control ACSF. This anoxic episode-induced pers istent potentiation of synaptic transmission lasted for more than 1 h and was termed anoxic LTP. 3 The anoxic episode induced a persistent p otentiation of the initial slopes of both pharmacologically isolated h a-amino-3-hydroxy-5-methyl-4-isoxazola-propionate (AMPA) receptor-medi ated e.p.s.p. (e.p.s.p.(AMPA)) and N-methyl-D-aspartate (NMDA) recepto r-mediated e.p.s.p. (e.p.s.p.(NMDA)) with a similar time course and ma gnitude. The sensitivity of postsynaptic neurones to NMDA (10 mu M), b ut not to AMPA (10 mu M) was also persistently potentiated following t he anoxic episode. In addition, the anoxia-induced LTP of the initial slope of e.p.s.p.(AMPA) was accompanied by a decrease in the magnitude of paired-pulse facilitation (PPF; from 106.8+/-17.6 to 46.6+/-18.4%, n=6), a phenomenon which was associated with presynaptic transmitter release mechanisms. 4 The induction of the anoxic LTP is dependent on the extracellular Ca2+ concentration. The induction of the anoxic LTP was completely abolished when the external Ca2+ was removed and substi tuted with equimolar Mg2+. Moreover, the anoxic LTP was completely abo lished in neurones intracellularly recorded with Ca2+ chelator bis-(O- aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA, 500 mM). 5 Occlusion experiments were performed to examine whether the sustained enhancemen t of the initial slope of the e.p.s.p. produced by tetanic stimulation and the anoxic episode share common cellular mechanisms. Three episod es of tetanic stimulation were delivered to saturate the LTP, followin g which a long period (15 min) of anoxia failed to cause a further pot entiation of the initial slope of the e.p.s.p. Similarly, prior induct ion of anoxic LTP also significantly attenuated the subsequent synapti c potentiation induced by a high-frequency tetanic stimulation (100 Hz for 1 s duration). These data imply that these two forms of synaptic plasticity may share a common cellular mechanism. 6 These results prov ide strong evidence that the generation of the anoxia-induced LTP of g lutamatergic synaptic transmission in the CA1 region of rat hippocampu s probably involves both of the presynaptic and postsynaptic loci. The mechanisms underlying the persistent potentiation are likely to be at tributable to an enhancement of presynaptic glutamate release and a se lective upregulation of postsynaptic NMDA receptor-mediated synaptic r esponse through the Ca2+-dependent processes.