Nitrous Oxide activates layer 5 prefrontal neurons via SK2 channel inhibition for antidepressant effect.

Nitrous oxide (NO) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled NO induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions.

Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids.

In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other mechanisms that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. In a recent study of the SSRIs fluvoxamine, fluoxetine and sertraline we found that, unlike the other two SSRIs, sertraline acutely inhibited LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocampal slices.

Synthesis and evaluation of photoaffinity labeling reagents for identifying binding sites of sulfated neurosteroids on NMDA and GABA receptors.

The endogenous neurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) are allosteric modulators of γ-aminobutyric acid type A (GABA) and -methyl-d-aspartate (NMDA) type glutamate receptors. Analogues of these endogenous steroid sulfates can be either positive or negative allosteric modulators (PAMs or NAMs, respectively) of these receptors, but there is limited information about the steroid-protein binding interactions that mediate these effects and photoaffinity labeling reagents (PALs) of sulfated steroids have not been reported previously. The synthesis of a panel of ten sulfated steroid analogues containing a diazirine group, five of which also contain an alkyne group for click chemistry reactions, for use in photoaffinity labeling studies to identify binding sites for steroid sulfates that are either positive or negative allosteric modulators is reported.

Nitrous Oxide Alters Functional Connectivity in Medial Limbic Structures in Treatment-Resistant Major Depression.

While nitrous oxide (NO) has demonstrated antidepressant properties in treatment-resistant major depression (TRD), little is known about neural mechanisms mediating these effects. Employing serial resting-state functional magnetic resonance imaging (rs-fMRI), we compared spatiotemporal effects of inhaled NO on brain functional connectivity in TRD patients (n=14) and non-depressed healthy controls (n=16, CNTL). Participants received sequential, one-hour inhalations of either 50% NO/oxygen or air/oxygen (placebo), with sessions separated by at least one month in random cross-over order.

Corrigendum: Glaucoma and microglia-induced neuroinflammation.

[This corrects the article DOI: 10.3389/fopht.2023.

δ-containing GABA receptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex.

Unlabelled: In medial prefrontal cortex (mPFC), fast-spiking parvalbumin (PV) interneurons regulate excitability and microcircuit oscillatory activity important for cognition. Although PV interneurons inhibit pyramidal neurons, they themselves express δ subunits of GABAA receptors important for slow inhibition. However, the specific contribution of δ-containing GABAA receptors to the function of PV interneurons in mPFC is unclear.

Neurosteroids mediate and modulate the effects of pro-inflammatory stimulation and toll-like receptors on hippocampal plasticity and learning.

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (μg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning.

A role for δ subunit-containing GABA receptors on parvalbumin positive neurons in maintaining electrocortical signatures of sleep states.

Unlabelled: GABA receptors containing δ subunits have been shown to mediate tonic/slow inhibition in the CNS. These receptors are typically found extrasynaptically and are activated by relatively low levels of ambient GABA in the extracellular space. In the mouse neocortex, δ subunits are expressed on the surface of some pyramidal cells as well as on parvalbumin positive (PV+) interneurons.

Effects of Complete and Partial Loss of the 24S-Hydroxycholesterol-Generating Enzyme on Behavior and Hippocampal Transcription in Mouse.

Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1.

Glyphosate as a direct or indirect activator of pro-inflammatory signaling and cognitive impairment.

Glyphosate-based herbicides are widely used around the world, making it likely that most humans have significant exposure. Because of habitual exposure, there are concerns about toxicity including neurotoxicity that could result in neurological, psychiatric, or cognitive impairment. We recently found that a single injection of glyphosate inhibits long-term potentiation, a cellular model of learning and memory, in rat hippocampal slices dissected 1 day after injection, indicating that glyphosate-based herbicides can alter cognitive function.

Endoplasmic reticulum stress, autophagy, neuroinflammation, and sigma 1 receptors as contributors to depression and its treatment.

The etiological factors contributing to depression and other neuropsychiatric disorders are largely undefined. Endoplasmic reticulum stress pathways and autophagy are well-defined mechanisms that play critical functions in recognizing and resolving cellular stress and are possible targets for the pathophysiology and treatment of psychiatric and neurologic illnesses. An increasing number of studies indicate the involvement of endoplasmic reticulum stress and autophagy in the control of neuroinflammation, a contributing factor to multiple neuropsychiatric illnesses.

Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation.

Cortical electroencephalograms (EEGs) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than excitation/inhibition ratio may alter EEG parameters.

Neuroactive steroid effects on autophagy in a human embryonic kidney 293 (HEK) cell model.

Neuropsychiatric and neurodegenerative disorders are correlated with cellular stress. Macroautophagy (autophagy) may represent an important protective pathway to maintain cellular homeostasis and functionality, as it targets cytoplasmic components to lysosomes for degradation and recycling. Given recent evidence that some novel psychiatric treatments, such as the neuroactive steroid (NAS) allopregnanolone (AlloP, brexanolone), may induce autophagy, we stably transfected human embryonic kidney 293 (HEK) cells with a ratiometric fluorescent probe to assay NAS effects on autophagy.

Persistent Brain Connectivity Changes in Healthy Volunteers Following Nitrous Oxide Inhalation.

Background: Nitrous oxide holds promise in the treatment of major depressive disorder. Its psychotropic effects and NMDA receptor antagonism have led to comparisons with ketamine. Despite longstanding use, persistent effects of nitrous oxide on the brain have not been characterized.

The herbicide glyphosate inhibits hippocampal long-term potentiation and learning through activation of pro-inflammatory signaling.

Glyphosate, a herbicide marketed as Roundup, is widely used but there are concerns this exposure could impair cognitive function. In the CA1 region of rat hippocampal slices, we investigated whether glyphosate alters synaptic transmission and long-term potentiation (LTP), a cellular model of learning and memory. Our hypothesis is that glyphosate alters neuronal function and impairs LTP induction via activation of pro-inflammatory processes.

Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation.

Unlabelled: Cortical electroencephalograms (EEG) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/ ) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition (E/I) balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than E/I ratio may alter EEG parameters.

The STOP COVID 2 Study: Fluvoxamine vs Placebo for Outpatients With Symptomatic COVID-19, a Fully Remote Randomized Controlled Trial.

Background: Prior randomized clinical trials have reported benefit of fluvoxamine ≥200 mg/d vs placebo for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: This randomized, double-blind, placebo-controlled, fully remote multisite clinical trial evaluated whether fluvoxamine prevents clinical deterioration in higher-risk outpatients with acute coronavirus disease 2019 (COVID-19). Between December 2020 and May 2021, nonhospitalized US and Canadian participants with confirmed symptomatic infection received fluvoxamine (50 mg on day 1, 100 mg twice daily thereafter) or placebo for 15 days.

The Taylor Family Institute at Washington University: Novel Treatments in Psychiatry.

Efforts to develop more effective treatments for psychiatric illnesses will require innovative approaches that address changes in brain networks underlying cognition, emotion and motivation, cardinal symptoms that cut across all psychiatric disorders. This effort will include new molecular entities that modulate neuronal excitability, synapses, cellular stress and inflammation. Other opportunities will come from repurposing existing treatments.

Striatal mGlu-mediated synaptic plasticity is independently regulated by location-specific receptor pools and divergent signaling pathways.

Metabotropic glutamate receptor 5 (mGlu) is widely expressed throughout the central nervous system and is involved in neuronal function, synaptic transmission, and a number of neuropsychiatric disorders such as depression, anxiety, and autism. Recent work from this lab showed that mGlu is one of a growing number of G protein-coupled receptors that can signal from intracellular membranes where it drives unique signaling pathways, including upregulation of extracellular signal-regulated kinase (ERK1/2), ETS transcription factor Elk-1, and activity-regulated cytoskeleton-associated protein (Arc). To determine the roles of cell surface mGlu as well as the intracellular receptor in a well-known mGlu synaptic plasticity model such as long-term depression, we used pharmacological isolation and genetic and physiological approaches to analyze spatially restricted pools of mGlu in striatal cultures and slice preparations.