Crosstalk between GABAA receptors in astrocytes and neurons triggered by general anesthetic drugs.

General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABAA) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABAA receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABAA receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABAA receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABAA receptors, which in turn promoted the release paracrine factors, that increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1ß and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1ß and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABAA receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway. Brief commentary BACKGROUND: Many older patients experience cognitive deficits after surgery. Anesthetic drugs may be a contributing factor as they cause a sustained increase in the function of "memory blocking" extrasynaptic GABAA receptors in neurons. Interestingly, astrocytes are required for this increase; however, the mechanisms underlying the astrocyte-to-neuron crosstalk remain unknown. TRANSLATIONAL SIGNIFICANCE: We discovered that commonly used general anesthetic drugs stimulate GABAA receptors in astrocytes, which in turn release paracrine factors that trigger a persistent increase in extrasynaptic GABAA receptor function in neurons via p38 MAPK. This novel form of crosstalk may contribute to persistent cognitive deficits after general anesthesia and surgery.

Physicians' Earnings Do Not Affect Their Online Ratings.

Objective: Physician-rating websites have exploded in popularity in recent years. Consequently, these sites have garnered attention from researchers interested in factors influencing patient satisfaction. A doctor's earnings might reflect practice patterns that could influence their patients' perceptions. We sought to explore any association between physicians' earnings and their online ratings. Methods: The names and billings of 500 physicians from British Columbia, Canada were randomly extracted from the 2016-17 BC Blue Book and matched to their profiles on RateMDs.com. Physicians' earnings were compared to their global ratings and to their Staff, Punctuality, Helpfulness, and Knowledge scores. Earnings and ratings were also compared between men and women, as well as between family medicine, surgical, and internal medicine and subspecialties cohorts. Results: We found no significant correlation between physicians' earnings and their global online ratings (p = 0.304). Weak negative correlations existed between earnings and Staff and Helpfulness ratings (Spearman's rho = -0.055, p < 0.001; rho = -0.033, p < 0.028). Online ratings were largely favorable (mean MD rating of 3.85/5. Male physicians earned significantly more than their female colleagues ($371,734.85 and $261,590.82, respectively; p < 0.001), but no significant difference existed between men and women with regards to online ratings (mean 3.87 and 3.81, respectively, p = 0.191). Surgical and Family Medicine specialties showed a negative correlation between income and ratings; no relationship was seen in the internal medicine and subspecialties cohort. Conclusions: No meaningful association was found between physicians' earnings and their online ratings, although there is an impact of specialty grouping. Patients tend to review doctors favorably online; these data add to the discussion of whether male and female doctors are differentially rated. Trends toward increased transparency in health care systems may help to elucidate how doctors' earnings influence patients' perception of and satisfaction with the care they receive.

Sustained increase in α5GABAA receptor function impairs memory after anesthesia.

Many patients who undergo general anesthesia and surgery experience cognitive dysfunction, particularly memory deficits that can persist for days to months. The mechanisms underlying this postoperative cognitive dysfunction in the adult brain remain poorly understood. Depression of brain function during anesthesia is attributed primarily to increased activity of γ-aminobutyric acid type A receptors (GABA(A)Rs), and it is assumed that once the anesthetic drug is eliminated, the activity of GABA(A)Rs rapidly returns to baseline and these receptors no longer impair memory. Here, using a murine model, we found that a single in vivo treatment with the injectable anesthetic etomidate increased a tonic inhibitory current generated by α5 subunit-containing GABA(A)Rs (α5GABA(A)Rs) and cell-surface expression of α5GABA(A)Rs for at least 1 week. The sustained increase in α5GABA(A)R activity impaired memory performance and synaptic plasticity in the hippocampus. Inhibition of α5GABA(A)Rs completely reversed the memory deficits after anesthesia. Similarly, the inhaled anesthetic isoflurane triggered a persistent increase in tonic current and cell-surface expression of α5GABA(A)Rs. Thus, α5GABA(A)R function does not return to baseline after the anesthetic is eliminated, suggesting a mechanism to account for persistent memory deficits after general anesthesia.