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Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons

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Abstract

Modulation of the standing outward current (I SO) by muscarinic acetylcholine (ACh) receptor (MAChR) stimulation is fundamental for the state-dependent change in activity mode of thalamocortical relay (TC) neurons. Here, we probe the contribution of MAChR subtypes, G proteins, phospholipase C (PLC), and two pore domain K+ (K2P) channels to this signaling cascade. By the use of spadin and A293 as specific blockers, we identify TWIK-related K+ (TREK)-1 channel as new targets and confirm TWIK-related acid-sensitve K+ (TASK)-1 channels as known effectors of muscarinic signaling in TC neurons. These findings were confirmed using a high affinity blocker of TASK-3 and TREK-1, namely, tetrahexylammonium chloride. It was found that the effect of muscarinic stimulation was inhibited by M1AChR-(pirenzepine, MT-7) and M3AChR-specific (4-DAMP) antagonists, phosphoinositide-specific PLCβ (PI-PLC) inhibitors (U73122, ET-18-OCH3), but not the phosphatidylcholine-specific PLC (PC-PLC) blocker D609. By comparison, depleting guanosine-5′-triphosphate (GTP) in the intracellular milieu nearly completely abolished the effect of MAChR stimulation. The block of TASK and TREK channels was accompanied by a reduction of the muscarinic effect on I SO. Current-clamp recordings revealed a membrane depolarization following MAChR stimulation, which was sufficient to switch TC neurons from burst to tonic firing under control conditions but not during block of M1AChR/M3AChR and in the absence of intracellular GTP. These findings point to a critical role of G proteins and PLC as well as TASK and TREK channels in the muscarinic modulation of thalamic activity modes.

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Acknowledgments

The authors thank E. Nass for excellent technical assistance. This work was supported by DFG (FOR 1086/2, TP2 to T. Budde and SGM, TP1 to T. Baukrowitz) and IZKF Münster (BU3/010/10 to TB).

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Correspondence to Thomas Budde.

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This article is published as part of the Special Issue on Sleep.

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Bista, P., Meuth, S.G., Kanyshkova, T. et al. Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons. Pflugers Arch - Eur J Physiol 463, 89–102 (2012). https://doi.org/10.1007/s00424-011-1056-9

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