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The Journal of Neuroscience, February 4, 2009, 29(5):1434-1445; doi:10.1523/JNEUROSCI.5574-08.2009

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Cellular/Molecular
Isoflurane-Sensitive Presynaptic R-Type Calcium Channels Contribute to Inhibitory Synaptic Transmission in the Rat Thalamus

Pavle M. Joksovic,¹ Marco Weiergräber,^4,5 WooYong Lee,^1,3 Henrik Struck,^4,5 Toni Schneider,^4,5 and Slobodan M. Todorovic^1,2

Departments of ¹Anesthesiology and ²Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0710, ³Department of Anesthesiology and Pain Medicine, InJe University, Sanggyepaik Hospital, Seoul 139-707, South Korea, and ⁴Department of Neurophysiology and ⁵Center for Molecular Medicine Cologne, University of Cologne, D-50931 Cologne, Germany

Correspondence should be addressed to Slobodan M. Todorovic, Department of Anesthesiology, University of Virginia Health System, Mail Box 800710, Charlottesville, VA 22908-0710. Email: st9d{at}virginia.edu

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 (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 Ca_V2.3 (1E) channels with an IC₅₀ of 206 ± 22 µM. Importantly, in vivo electroencephalographic (EEG) recordings in adult Ca_V2.3 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.

Key words: anesthesia; calcium channels; calcium current; GABA_A receptor; GABAergic neuron; thalamus

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Received Nov. 20, 2008; revised Dec. 29, 2008; accepted Jan. 6, 2009.

Correspondence should be addressed to Slobodan M. Todorovic, Department of Anesthesiology, University of Virginia Health System, Mail Box 800710, Charlottesville, VA 22908-0710. Email: st9d{at}virginia.edu

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