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Figure 3 | BMC Neuroscience

Figure 3

From: Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices

Figure 3

Anesthetics act at several sites to depress CA1 neuron synaptically evoked discharge. (A) Halothane appears to act presynaptically to depress glutamate release, evidenced by an increase in paired pulse facilitation concomitant with EPSP depression. A similar increase in facilitation was produced by isoflurane and pentobarbital, but not by thiopental or propofol. No change in EPSP rise or decay time was apparent in the presence any anesthetic. (B) The increased facilitation produced by halothane, isoflurane and pentobarbital was not reversed by bicuculline (BIC) indicating a depressant effect on glutamate nerve terminals – independent of anesthetic effects at GABAA receptors. (C) Differential GABA effects were also evident for paired pulse inhibition of population spike responses. Volatile agents like halothane produced little or no paired pulse inhibition at concentrations that produced a half maximal depression of first pulse responses. In contrast, propofol increased paired pulse inhibition and similar effects were observed with thiopental and pentobarbital. This increase in paired pulse inhibition was reversed by bicuculline indicating that these anesthetics enhanced recurrent GABAA-mediated inhibition. (D) The anesthetics also appeared to act directly on CA1 pyramidal neuron membrane excitability to slow action potential discharge activity, although the intravenous agents were much more effective compared to volatile anesthetics. None of the anesthetics produced an appreciable effect on individual action potential amplitude or time course (right: control – solid line; anesthetic – dotted, for halothane on top and propofol on bottom). (E) Anesthetics act at multiple sites to depress the CA1 neuron circuit. Sites of action are indicated on a diagram of CA1 circuitry showing input from Schaffer-collateral fibers, local inhibitory interneurons (IN) and a CA1 pyramidal neuron (triangle). Action potential propagation in Schaffer-collateral fibers (1) was depressed by ~ 15% by halothane and this contributes about 25 % to EPSP depression [60, 61]; see also [17]. This effect did not contribute to anesthetic-induced increases in facilitation, because no change in facilitation occurred when a comparable amount of action potential depression was produced by tetrodotoxin [61]. Further presynaptic depression at glutamate nerve terminals (2) was evident from the increased facilitation observed (Fig. 3A&3B) and there is also good evidence for postsynaptic depressant effects on both NMDA and AMPA receptors (3) [16, 19, 62, 63]. Anesthetics also act pre- and postsynaptically at GABA-mediated synapses (4, see Fig. 2) and can also increase tonic GABA-mediated inhibition by acting as GABA agonists in the absence of synaptically released GABA (5) [46-48]. Perisynaptic and extrasynaptic tonic GABAA receptors (7) also contribute to the postsynaptic depression produced by isoflurane [64] as well as thiopental and propofol [4, 65]. Enhanced recurrent inhibition (6) plays and important role for anesthetics in vivo [45] and strong effects were evident in the present study for propofol, thiopental and pentobarbital (Fig. 3C), similar to effects previously reported for halothane in hippocampal slices [26]. In addition, anesthetics also directly depress CA1 neuron excitability by blocking calcium channels and enhancing potassium currents contributing to hyperpolarization (8) and increased discharge thresholds [40, 41, 42, also Nishikawa, Beida & Maclver, unpublished]. These latter effects could influence CA1 neuron discharge activity for near threshold responses, but for the stronger stimuli used in the present study, effects on GABA and glutamate synapses and on postsynaptic receptors for these transmitters appear to contribute most (~ 80 %) to the depressant actions observed.

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