TY - JOUR T1 - Isoflurane-Sensitive Presynaptic R-Type Calcium Channels Contribute to Inhibitory Synaptic Transmission in the Rat Thalamus JF - The Journal of Neuroscience JO - J. Neurosci. SP - 1434 LP - 1445 DO - 10.1523/JNEUROSCI.5574-08.2009 VL - 29 IS - 5 AU - Pavle M. Joksovic AU - Marco Weiergräber AU - WooYong Lee AU - Henrik Struck AU - Toni Schneider AU - Slobodan M. Todorovic Y1 - 2009/02/04 UR - http://www.jneurosci.org/content/29/5/1434.abstract N2 - 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 GABAA receptors, isoflurane prolonged the decay-time constants of both eIPSCs and mIPCSs. Surprisingly, isoflurane completely inhibited the amplitude of eIPSCs at clinically relevant concentrations (IC50 of 240 ± 20 μm), 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 μm nickel (Ni2+) and the more specific R-type Ca2+ channel blocker SNX-482 (0.5 μm) decreased eIPSC amplitudes, increased the paired-pulse ratio, and attenuated isoflurane-induced inhibition of eIPSCs. In addition, isoflurane potently blocked currents in recombinant human CaV2.3 (α1E) channels with an IC50 of 206 ± 22 μm. Importantly, in vivo electroencephalographic (EEG) recordings in adult CaV2.3 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 Ca2+ channels may contribute to the clinical effects of general anesthesia. ER -