Isoflurane depresses hippocampal CA1 glutamate nerve terminals without inhibiting fiber volleys

Isoflurane (350 μM; 1 MAC) reversibly depressed EPSP amplitudes by ~60% while facilitation increased ~20%. Consistent with previous studies, these results indicate a presynaptic site of action that involves reduced excitation-release coupling. EPSPs were depressed to comparable levels by TTX (60 nM) or lowered stim, but facilitation was not changed, indicating a simple failure of axonal conduction. Similarly, partial antagonism of postsynaptic glutamate receptors with CNQX (10 μM) depressed EPSP amplitudes with no change in facilitation. However, EPSP depression by low external Ca2+ (0.8 mM) was accompanied by an increase in facilitation comparable to isoflurane. Isoflurane depression of EPSP amplitudes could also be partly reversed by high external Ca2+ (4 mM) that also decreased facilitation. Isoflurane or low Ca2+ markedly reduced the slopes of fiber volley (FV)-EPSP input-output curves, consistent with little or no effect on FVs. By contrast, TTX didn't alter the FV-EPSP curve slope, indicating that EPSP depression resulted from FV depression. FVs were remarkably resistant to isoflurane. Somatic spike currents were unaffected by 350 μM (1 MAC) isoflurane as well. The EC50 for isoflurane depression of FVs was ~2.8 mM (12 vol. %; 8 MAC).Isoflurane appears to depress CA1 synapses at presynaptic sites downstream from Na channels, as evident by the increased facilitation that accompanies EPSP depression. Fiber volleys did not exhibit depression by isoflurane, as has been reported for other brain regions.A longstanding controversy in the anesthesia literature concerns whether general anesthetics exert their actions primarily by depression of synaptic transmission or by blocking nerve conduction like local anesthetics. Thesleff [1] first proposed that general and local anesthetics share a common mechanism to block Na conductance [cf. [2-4]]. Alternatively, other early studies yielded evidence that volatile anesthetics preferentially depress synaptic potentials rather t