Daniel Mulkey

Daniel Mulkey

Daniel Mulkey

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Anesthetics are chemically diverse, yet they all have similar effects on the state of consciousness, and so for decades research has sought to identify a single underlying mechanism to explain how anesthetics work. However, this effort has given way to the ‘multiple target hypothesis’ as it became clear that anesthetics can target specific cellular proteins (e.g., GABA_A receptors, glycine receptors, glutamate receptors, HCN channels, voltage-independent K⁺channels and voltage-dependent K⁺, Ca²⁺ and Na⁺ channels to name a few; for a review see {1-3}) to alter neural function and result in the characteristic features of general anesthesia.  However, despite evidence that astrocytes are capable of modulating multiple aspects of neural function {4}, and have been shown to exhibit Ca²⁺ transients in response to wake-on neurotransmitters, suggesting involvement in maintenance of wakefulness {5}, they have been largely ignored as potential targets of anesthesia. 
 
The goal of this study was to determine whether three commonly used anesthetics with different putative neural targets (isoflurane, ketamine/xylazine and urethane) can effect Ca²⁺ dynamics in cortical astrocytesin vivo. By monitoring astrocyte Ca²⁺ events in the soma and processes by two-photon laser-scanning microscopy while simultaneously monitoring neural activity by electrocorticographic recording, they show that i) all three anesthetics suppressed spontaneous and evoked astrocyte Ca²⁺ transients in both regions of interest; ii) astrocytes are highly and selectively sensitive to these anesthetics, as evidenced by blockade of evoked Ca²⁺ responses in astrocytes at concentrations that do not blunt neural responses; and iii) astrocyte Ca²⁺ signaling is dependent on IP₃R2 signaling but not neural activity.
 
These results show that isoflurane, ketamine/xylazine and urethane collectively target astrocytes to suppress Ca²⁺ signaling by a mechanism that appears independent of neural activity, and in doing so identify astrocytes as novel common targets of anesthetics. Furthermore, since astrocytes are ubiquitously expressed throughout the brain and astrocyte Ca²⁺ signaling may be required for maintenance of wakefulness, perhaps anesthetic-dependent suppression of astrocyte Ca²⁺ dynamics serves as the long-sought common mechanism for general anesthesia. This study also supports the possibility that IP₃R2 mediated release of Ca²⁺ from intracellular stores is a requisite feature of astrocyte Ca²⁺ signaling; however, it remains to be determined whether anesthetics directly interact with this receptor or indirectly effect Ca²⁺signaling by one or more mechanisms.