General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex

Abstract

Calcium signaling represents the principle pathway by which astrocytes respond to neuronal activity. General anesthetics are routinely used in clinical practice to induce a sleep-like state, allowing otherwise painful procedures to be performed. Anesthetic drugs are thought to mainly target neurons in the brain and act by suppressing synaptic activity. However, the direct effect of general anesthesia on astrocyte signaling in awake animals has not previously been addressed. This is a critical issue, because calcium signaling may represent an essential mechanism through which astrocytes can modulate synaptic activity. In our study, we performed calcium imaging in awake head-restrained mice and found that three commonly used anesthetic combinations (ketamine/xylazine, isoflurane, and urethane) markedly suppressed calcium transients in neocortical astrocytes. Additionally, all three anesthetics masked potentially important features of the astrocyte calcium signals, such as synchronized widespread transients that appeared to be associated with arousal in awake animals. Notably, anesthesia affected calcium transients in both processes and soma and depressed spontaneous signals, as well as calcium responses, evoked by whisker stimulation or agonist application. We show that these calcium transients are inositol 1,4,5-triphosphate type 2 receptor (IP 3 R2)-dependent but resistant to a local blockade of glutamatergic or purinergic signaling. Finally, we found that doses of anesthesia insufficient to affect neuronal responses to whisker stimulation selectively suppressed astrocyte calcium signals. Taken together, these data suggest that general anesthesia may suppress astrocyte calcium signals independently of neuronal activity. We propose that these glial effects may constitute a nonneuronal mechanism for sedative action of anesthetic drugs.

Rapid stimulus-evoked astrocyte Ca 2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo

“…This activity comprised two types of events, a fast and a slow rise in Ca 2+ levels, which were clearly separable because of their distinct temporal characteristics. Slow astrocytic Ca 2+ responses have been reported previously (13,(31)(32)(33). The majority of the fast, high-frequency signals could be identified only after superposition of data points recorded during a stimulation train, which might explain why fast astrocytic Ca 2+ signals have so seldom been reported in vivo (9) and emphasizes the relevance of the method of analysis applied here.…”

“…mGluR5a activation leads to increased cytosolic Ca 2+ by IP 3 -mediated release from endoplasmic reticulum (32,33) and could be the pathway from stimulation to rapid Ca 2+ responses in astrocytes. The presence of mGluR5a in astrocytes in adult mouse cortex is debated (8,39), and we cannot exclude that the effect of the mGluR5 receptor antagonist on Ca 2+ signals in our experiments is indirect, i.e., via an effect of synaptic transmission.…”

Long-term In Vivo Calcium Imaging of Astrocytes Reveals Distinct Cellular Compartment Responses to Sensory Stimulation

“…Processes have a close proximity to synapses, and the size of astrocyte domain activation could be an integral feature of how astrocytes encode local synaptic activity. It is also worth noting that anesthetics can inhibit astrocyte calcium signals (Thrane et al 2012), which could have suppressed the calcium responses in our experiments. However, we found that the responses were consistent across animals under isoflurane anesthesia.…”

Quantum Wave Information of Life Revealed: An Algorithm for Electromagnetic Frequencies that Create Stability of Biological Order, With Implications for Brain Function and Consciousness

“…It has also become clear that the brain should not be seen solely as a collections of neurons, but rather as a fractal network of a tripartite structure of neurons, glial cells and astrocytes, that intensively communicate, among others by Ca2+ fluxes (Pereira, 2010;Bieberich, 2012), even explaining the mechanism of general anesthesia (Thrane et al, 2012). For a rapid and causally effective flux of information, as well as a continuous updating of a personal information domain, a "bi-cyclic" mental workspace was conceived, housing interacting and entangled wave and protein-based transitions that build-up and retrieve information from a universal knowledge domain (Meijer, 2014).…”