Discovering the Intriguing Properties of Extrasynaptic γ-Aminobutyric Acid Type A Receptors.

Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. By Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Proc Natl Acad Sci U S A 2004; 101:3662-7. Reprinted with permission. In this Classic Paper Revisited, the author recounts the scientific journey leading to a report published in the Proceedings of the National Academy of Sciences (PNAS) and shares several personal stories from her formative years and "research truths" that she has learned along the way. Briefly, the principal inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), was conventionally thought to regulate cognitive processes by activating synaptic GABA type A (GABAA) receptors and generating transient inhibitory synaptic currents. However, the author's laboratory team discovered a novel nonsynaptic form of tonic inhibition in hippocampal pyramidal neurons, mediated by extrasynaptic GABAA receptors that are pharmacologically distinct from synaptic GABAA receptors. This tonic current is highly sensitive to most general anesthetics, including sevoflurane and propofol, and likely contributes to the memory-blocking properties of these drugs. Before the publication in PNAS, the subunit composition of GABAA receptors that generate the tonic current was unknown. The team's research showed that GABAA receptors containing the α5 subunit (α5GABAARs) generated the tonic inhibitory current in hippocampal neurons. α5GABAARs are highly sensitive to GABA, desensitize slowly, and are thus well suited for detecting low, persistent, ambient concentrations of GABA in the extracellular space. Interest in α5GABAARs has surged since the PNAS report, driven by their pivotal roles in cognitive processes and their potential as therapeutic targets for treating various neurologic disorders.

Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care.

During the last 100 years, the role of anesthesiologists in psychiatry has focused primarily on facilitating electroconvulsive therapy and mitigating postoperative delirium and other perioperative neurocognitive disorders. The discovery of the rapid and sustained antidepressant properties of ketamine, and early results suggesting that other general anesthetic drugs (including nitrous oxide, propofol, and isoflurane) have antidepressant properties, has positioned anesthesiologists at a new frontier in the treatment of neuropsychiatric disorders. Moreover, shared interest in understanding the biologic underpinnings of anesthetic drugs as psychotropic agents is eroding traditional academic boundaries between anesthesiology and psychiatry. This article presents a brief overview of anesthetic drugs as novel antidepressants and identifies promising future candidates for the treatment of depression. The authors issue a call to action and outline strategies to foster collaborations between anesthesiologists and psychiatrists as they work toward the common goals of repurposing anesthetic drugs as antidepressants and addressing mood disorders in surgical patients.

Self-harm presentations to hospital trauma centre emergency departments during the first year of the COVID-19 pandemic.

The COVID-19 pandemic raised concerns regarding increased suicide-related behaviours. We compared characteristics and counts of Emergency Department (ED) presentations for self-harm, an important suicide-related outcome, during versus prior to the pandemic's first year. We included patients presenting with self-harm to the ED of two trauma centres in Toronto, Canada. Time series models compared intra-pandemic (March 2020-February 2021) presentation counts to predictions from pre-pandemic data. The self-harm proportion of ED presentations was compared between the intra-pandemic period and preceding three years. A retrospective chart review of eligible patients seen from March 2019-February 2021 compared pre- vs. intra-pandemic patient and injury characteristics. While monthly intra-pandemic self-harm counts were largely within expected ranges, the self-harm proportion of total presentations increased. Being widowed (OR=9.46; 95 %CI=1.10-81.08), employment/financial stressors (OR=1.65, 95 %CI=1.06-2.58), job loss (OR=3.83; 95 %CI=1.36-10.76), and chest-stabbing self-harm (OR=2.50; 95 %CI=1.16-5.39) were associated with intra-pandemic presentations. Intra-pandemic self-harm was also associated with Intensive Care Unit (ICU) admission (OR=2.18, 95 %CI=1.41-3.38). In summary, while the number of self-harm presentations to these trauma centres did not increase during the early pandemic, their proportion was increased. The association of intra-pandemic self-harm with variables indicating medically severe injury, economic stressors, and being widowed may inform future suicide and self-harm prevention strategies.