Annu Rev Physiol

Information processing imposes urgent metabolic demands on neurons, which have negligible energy stores and restricted access to fuel. Here, we discuss metabolic recruitment, the tissue-level phenomenon whereby active neurons harvest resources from their surroundings. The primary event is the neuronal release of K+ that mirrors workload. Astrocytes sense K+ in exquisite fashion thanks to their unique coexpression of NBCe1 and α2β2 Na+/K+ ATPase, and within seconds switch to Crabtree metabolism, involving GLUT1, aerobic glycolysis, transient suppression of mitochondrial respiration, and lactate export. The lactate surge serves as a secondary recruiter by inhibiting glucose consumption in distant cells. Additional recruiters are glutamate, nitric oxide, and ammonium, which signal over different spatiotemporal domains. The net outcome of these events is that more glucose, lactate, and oxygen are made available. Metabolic recruitment works alongside neurovascular coupling and various averaging strategies to support the inordinate dynamic range of individual neurons. Copyright © 2023 by the author(s)

Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis

Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.publishedVersio

Subcellular specificity of cannabinoid effects in striatonigral circuits

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Essays Biochem

Astrocytes are key players in brain homeostasis and function. During the last years, several studies have cemented this notion by showing that these cells respond to neuronal signals and, via the release of molecules that modulate and support synaptic activity (gliotransmission) participates in the functions of the so-called tripartite synapse. Thus, besides their established control of brain metabolism, astrocytes can also actively control synaptic activity and behavior. Among the signaling pathways that shape the functions of astrocyte, the cannabinoid type-1 (CB1) receptor is emerging as a critical player in the control of both gliotransmission and the metabolic cooperation between astrocytes and neurons. In the present short review, we describe known and newly discovered properties of the astroglial CB1 receptors and their role in modulating brain function and behavior. Based on this evidence, we finally discuss how the functions and mode of actions of astrocyte CB1 receptors might represent a clear example of the inextricable relationship between energy metabolism and gliotransmission. These tight interactions will need to be taken into account for future research in astrocyte functions and call for a reinforcement of the theoretical and experimental bridges between studies on metabolic and synaptic functions of astrocytes. © 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society

CB1R-dependent regulation of astrocyte physiology and astrocyte-neuron interactions

The endocannabinoid system (ECS) is involved in a variety of brain functions, mainly through the activation of the type-1 cannabinoid receptors (CB1R). CB1R are highly expressed throughout the brain at different structural, cellular and subcellular locations and its activity and expression levels have a direct impact in synaptic activity and behavior. In the last few decades, astrocytes have arisen as active players of brain physiology through their participation in the tripartite synapse and through their metabolic interaction with neurons. Here, we discuss some of the mechanisms by which astroglial CB1R at different subcellular locations, regulate astrocyte calcium signals and have an impact on gliotransmission and metabolic regulation. In addition, we discuss evidence pointing at astrocytes as potential important sources of endocannabinoid synthesis and release. Thus, we summarize recent findings that add further complexity and establish that the ECS is a fundamental effector of astrocyte functions in the brain. This article is part of the special issue on ‘Cannabinoids'.Dissection des mécanismes hypothalamiques impliqués dans la détection du statut nutritionnel et régulation de la prise alimentaire via les interactions entre mTORC1, les mélanocortines et les endocannabinoïdes.Représentation sensorielle lors d'états psychotiquesRecepteurs aux cannabinoides dans le codage visuel corticalRôle du récepteur aux cannabinoïdes de type 1 mitochondriale dans les circuits hypothalamiques et son interaction avec la voie mTORC1 dans l'obésité.Bordeaux Region Aquitaine Initiative for Neuroscienc

Bidirectional astrocytic GLUT1 activation by elevated extracellular K+

The acute rise in interstitial K+ that accompanies neural activity couples the energy demand of neurons to the metabolism of astrocytes. The effects of elevated K+ on astrocytes include activation of aerobic glycolysis, inhibition of mitochondrial respiration and the release of lactate. Using a genetically encoded FRET glucose sensor and a novel protocol based on 3-O-methylglucose trans-acceleration and numerical simulation of glucose dynamics, we report that extracellular K+ is also a potent and reversible modulator of the astrocytic glucose transporter GLUT1. In cultured mouse astrocytes, the stimulatory effect developed within seconds, engaged both the influx and efflux modes of the transporter, and was detected even at 1 mM incremental K+. The modulation of GLUT1 explains how astrocytes are able to maintain their glucose pool in the face of strong glycolysis stimulation. We propose that the stimulation of GLUT1 by K+ supports the production of lactate by astrocytes and the timely delivery of glucose to active neurons

Channel-Mediated Lactate Release by K+-Stimulated Astrocytes

Excitatory synaptic transmission is accompanied by a local surge in interstitial lactate that occurs despite adequate oxygen availability, a puzzling phenomenon termed aerobic glycolysis. In addition to its role as an energy substrate, recent studies have shown that lactate modulates neuronal excitability acting through various targets, including NMDA receptors and G-protein-coupled receptors specific for lactate, but little is known about the cellular and molecular mechanisms responsible for the increase in interstitial lactate. Using a panel of genetically encoded fluorescence nanosensors for energy metabolites, we show here that mouse astrocytes in culture, in cortical slices, and in vivo maintain a steady-state reservoir of lactate. The reservoir was released to the extracellular space immediately after exposure of astrocytes to a physiological rise in extracellular K+ or cell depolarization. Cell-attached patch-clamp analysis of cultured astrocytes revealed a 37 pS lactate-permeable ion channel activated by cell depolarization. The channel was modulated by lactate itself, resulting in a positive feedback loop for lactate release. A rapid fall in intracellular lactate levels was also observed in cortical astrocytes of anesthetized mice in response to local field stimulation. The existence of an astrocytic lactate reservoir and its quick mobilization via an ion channel in response to a neuronal cue provides fresh support to lactate roles in neuronal fueling and in gliotransmission

Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF

BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes