Isoflurane-sensitive presynaptic R-type calcium channels contribute to inhibitory synaptic transmission in the rat thalamus.
Because inhibitory synaptic transmission is a major mechanism of general anesthesia, we examined the effects of isoflurane on properties of GABAergic inhibitory currents in the reticular thalamic nucleus (nRT) in brain slices. The evoked IPSCs (eIPSCs) and spontaneous miniature synaptic currents (mIPSCs) of visualized nRT cells in young and adult rats were recorded. Consistent with postsynaptic effects on GABA(A) receptors, isoflurane prolonged the decay-time constants of both eIPSCs and mIPCSs. Surprisingly, isoflurane completely inhibited the amplitude of eIPSCs at clinically relevant concentrations (IC(50) of 240+/-20 microm), increased the paired-pulse ratio, and decreased the frequency of mIPSCs, indicating that presynaptic mechanisms may also contribute to the effects of isoflurane on IPSCs. The overall effect of isoflurane on eIPSCs in nRT cells was a decrease of net charge-transfer across the postsynaptic membrane. The application of 100 microm nickel (Ni(2+)) and the more specific R-type Ca(2+) channel blocker SNX-482 (0.5 microm) decreased eIPSC amplitudes, increased the paired-pulse ratio, and attenuated isoflurane-induced inhibition of eIPSCs. In addition, isoflurane potently blocked currents in recombinant human Ca(V)2.3 (alpha1E) channels with an IC(50) of 206 +/- 22 mum. Importantly, in vivo electroencephalographic (EEG) recordings in adult Ca(V)2.3 knock-out mice demonstrated alterations in isoflurane-induced burst-suppression activity. Because the thalamus has a key function in processing sensory information, sleep, and cognition, modulation of its GABAergic tone by presynaptic R-type Ca(2+) channels may contribute to the clinical effects of general anesthesia.
Joksovic
Pavle M
PM
Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0710, USA.
Weiergräber
Marco
M
Lee
WooYong
W
Struck
Henrik
H
Schneider
Toni
T
Todorovic
Slobodan M
SM
D000818:Animals; D020908:Calcium Channels, R-Type / Q000502:physiology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D007530:Isoflurane / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013788:Thalamus / Q000187:drug effects / Q000502:physiology*
D020908:Calcium Channels, R-Type; D007530:Isoflurane