Review
Biochemistry & Molecular Biology
Fiorenzo Conti, Daniela Pietrobon
Summary: Glutamate transporters play a crucial role in regulating glutamate levels in the brain and are involved in various brain functions and neurological diseases. Familial hemiplegic migraine type 2 (FHM2) is a rare form of migraine with aura caused by loss-of-function mutations in alpha 2NKA. FHM2 mice exhibit reduced expression of glutamate transporters and impaired glutamate clearance, leading to enhanced susceptibility to cortical spreading depression and increased pain response to migraine triggers.
NEUROCHEMICAL RESEARCH
(2023)
Article
Multidisciplinary Sciences
Shan Yao, Min-Dong Xu, Ying Wang, Shen-Ting Zhao, Jin Wang, Gui-Fu Chen, Wen-Bing Chen, Jian Liu, Guo-Bin Huang, Wen-Juan Sun, Yan-Yan Zhang, Huan-Li Hou, Lei Li, Xiang-Dong Sun
Summary: The authors report a glycolytic deficit in mice under social stress, which is associated with depressive-like behaviors. They demonstrate that astrocytic LDHA affects neuronal excitability and the production of L-lactate, and this plays a role in preventing depressive-like behaviors. Mechanistic studies reveal that L-lactate promotes neuronal excitability through MCT2 and by inhibiting BK channels.
NATURE COMMUNICATIONS
(2023)
Article
Neurosciences
Jarand B. B. Hjukse, Mario F. D. L. Puebla, Gry Fluge Vindedal, Rolf Sprengel, Vidar Jensen, Erlend A. A. Nagelhus, Wannan Tang
Summary: Astrocytes, a type of glial cells, interact with nearby neurons in a complex way. This study used imaging techniques to observe the response of astrocytes and neurons during high-frequency stimulation of neural circuits. Results showed that increasing levels of released glutamate led to accelerated calcium elevation in astrocytes, and this response was not directly dependent on glutamate transporters. Instead, astrocytic calcium elevation was indirectly associated with the uptake of extracellular glutamate. In addition, the study also revealed the involvement of Na+/Ca2+ exchanger and membrane P2X receptors in the astrocytic calcium response.
Review
Cell Biology
Sairaj Satarker, Sree Lalitha Bojja, Prasada Chowdari Gurram, Jayesh Mudgal, Devinder Arora, Madhavan Nampoothiri
Summary: This article reviews the different mechanisms of astrocytic glutamate release and their implications in neurodegenerative diseases. Regulating astrocytic glutamatergic transmission could provide new approaches for the treatment of these diseases.
Review
Clinical Neurology
Oscar B. Alcoreza, Dipan C. Patel, Bhanu P. Tewari, Harald Sontheimer
Summary: This review highlights the critical role of astrocytes in regulating glutamate, altering extracellular space volume, and influencing neuronal excitability in epilepsy. It also discusses the mechanisms by which ambient glutamate can affect neuronal function and the upregulation of System xc- and changes in glutamate receptor expression in epileptic tissue.
FRONTIERS IN NEUROLOGY
(2021)
Article
Multidisciplinary Sciences
Marinus Toman, John Joseph Wade, Alexei Verkhratsky, Mark Dallas, Angela Bithell, Bronac Flanagan, Jim Harkin, Liam McDaid
Summary: In this study, a computational model is used to investigate the impact of the spatial relationship between astrocytes and synapses on ionic homeostasis. The results show that the degree of astrocyte coverage affects the concentrations of K+, Na+, and Ca2+, particularly the uptake of Ca2+. Moreover, the proximity of astrocytic leaflets to the synaptic cleft determines the formation of Ca2+ microdomains, which may affect leaflet motility.
SCIENTIFIC REPORTS
(2023)
Article
Pharmacology & Pharmacy
Shu-Man Pan, Yi-Fan Zhou, Na Zuo, Rui-Qing Jiao, Ling-Dong Kong, Ying Pan
Summary: Fluoxetine improves glucose uptake and glycolysis in astrocytes by restricting the GR-TXNIP-GLUT1 pathway, thereby alleviating corticosterone-induced depression.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Clinical Neurology
Thulani Palpagama, Aimee Rose Mills, Mackenzie Wendy Ferguson, Praju Vikas Ankeal, Clinton Turner, Lynette Tippett, Bert van Der Werf, Henry John Waldvogel, Richard Lewis Maxwell Faull, Andrea Kwakowsky
Summary: This study investigates the correlation between neurodegenerative changes in the midcingulate cortex and mood symptoms in patients with Huntington's disease. The results show alterations in the number and morphology of activated microglia in patients with Huntington's disease who present with mood symptoms. Additionally, astrocytes in these patients also exhibit changes. These findings are important for understanding the neuroinflammatory mechanisms in Huntington's disease and developing targeted therapeutics.
ANNALS OF NEUROLOGY
(2023)
Article
Immunology
Yosuke Danjo, Eiji Shigetomi, Yukiho J. Hirayama, Kenji Kobayashi, Tatsuya Ishikawa, Yugo Fukazawa, Keisuke Shibata, Kenta Takanashi, Bijay Parajuli, Youichi Shinozaki, Sun Kwang Kim, Junichi Nabekura, Schuichi Koizumi
Summary: The activation of astrocytes plays a crucial role in brain plasticity and the development of neurological disorders. The presence of mGluR5 in astrocytes, which is absent under normal conditions, is essential for regulating synaptic plasticity and neuronal activity, particularly in the somatosensory cortex.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Neurosciences
Giovanna Crivellaro, Angelita Tottene, Marina Vitale, Marcello Melone, Giorgio Casari, Fiorenzo Conti, Mirko Santello, Daniela Pietrobon
Summary: Migraine is a common but poorly understood sensory circuit disorder. Mouse models of familial hemiplegic migraine show increased susceptibility to cortical spreading depression, which is mainly caused by reduced expression of astrocytic Na+, K+-ATPases. The enhanced NMDAR activation in FHM2 mice is activity-dependent and can be rescued by inhibition of GluN1-N2B NMDARs.
NEUROBIOLOGY OF DISEASE
(2021)
Article
Endocrinology & Metabolism
Brenda Morant-Ferrando, Daniel Jimenez-Blasco, Paula Alonso-Batan, Jesus Agulla, Rebeca Lapresa, Dario Garcia-Rodriguez, Sara Yunta-Sanchez, Irene Lopez-Fabuel, Emilio Fernandez, Peter Carmeliet, Angeles Almeida, Marina Garcia-Macia, Juan P. P. Bolanos
Summary: Astrocytes, a type of glial cells in the brain, primarily rely on glycolysis for energy production, indicating glucose as their main metabolic precursor. However, recent studies have shown that astrocytes also have the ability to metabolize fatty acids, and this metabolic pathway may play a role in preserving mitochondrial function and cognitive performance.
Article
Multidisciplinary Sciences
Verena Untiet, Felix R. M. Beinlich, Peter Kusk, Ning Kang, Antonio Ladron-de-Guevara, Wei Song, Celia Kjaerby, Mie Andersen, Natalie Hauglund, Zuzanna Bojarowska, Bjorn Sigurdsson, Saiyue Deng, Hajime Hirase, Nicolas C. C. Petersen, Alexei Verkhratsky, Maiken Nedergaard
Summary: Information transfer within neuronal circuits depends on the balance and recurrent activity of excitatory and inhibitory neurotransmission. Astrocytes, a type of glial cell, act as a dynamic Cl- reservoir regulating Cl- homeostasis in the central nervous system (CNS). Intracellular chloride concentration in astrocytes is higher and more stable during sleep, while it is lower and fluctuates in response to sensory input and motor activity during wakefulness. Efflux of Cl- from astrocytes supports inhibitory transmission in the CNS.
NATURE COMMUNICATIONS
(2023)
Article
Neurosciences
Lea Fritschi, Johanna Hedlund Lindmar, Florian Scheidl, Kerstin Lenk
Summary: According to the tripartite synapse model, astrocytes play a modulatory role in neuronal signal transmission and dysfunction of astrocytes has been linked to psychiatric diseases such as schizophrenia. Various hypotheses have been proposed regarding the pathological mechanisms of astrocytes in schizophrenia, including altered glutamate transmission. However, there is still no consensus on the molecular pathways and network mechanisms altered in schizophrenia. Computational models have shown that impairment of both neurons and astrocytes disrupts neuronal network activity in schizophrenia.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Article
Neurosciences
Chiara Cervetto, Guido Maura, Diego Guidolin, Sarah Amato, Cristina Ceccoli, Luigi F. Agnati, Manuela Marcoli
Summary: It is now widely accepted that astrocytes have an active role in synaptic transmission, leading to a shift towards a neuro-astrocentric perspective in the central nervous system. Astrocytes respond to synaptic activity, releasing gliotransmitters and expressing neurotransmitter receptors, making them co-actors with neurons in signal communication. The interaction between G protein-coupled receptors through heteromerization has been extensively studied at neuronal plasma membrane and has changed the understanding of signal communication in the central nervous system.
Article
Biochemistry & Molecular Biology
Markus P. Kummer, Christina Ising, Christiane Kummer, Heela Sarlus, Angelika Griep, Ana Vieira-Saecker, Stephanie Schwartz, Annett Halle, Matthias Bruckner, Kristian Handler, Joachim L. Schultze, Marc Beyer, Eicke Latz, Michael T. Heneka
Summary: Research indicates that upregulated expression of PD-L1 and PD-1 is found around amyloid plaques in Alzheimer's disease patients and mouse models. Deletion of microglial PD-1 leads to inflammatory responses and impairs Aβ uptake, contributing to increased deposition of Aβ plaques. This highlights the role of ineffective immune regulation by the PD-1/PD-L1 axis in chronic neuroinflammation associated with Alzheimer's disease.
Article
Biochemistry & Molecular Biology
L. Felipe Barros, Ivan Ruminot, Alejandro San Martin, Rodrigo Lerchundi, Ignacio Fernandez-Moncada, Felipe Baeza-Lehnert
Summary: This article discusses the interdependent biochemical phenomena of Pasteur effect, Warburg effect, and Crabtree effect in brain cells, and their association with aerobic glycolysis. Research indicates that astrocytes play a key role in aerobic glycolysis, providing more energy to neurons, while neurons regulate energy metabolism by maintaining a balance between glucose and lactate.
NEUROCHEMICAL RESEARCH
(2021)
Article
Neurosciences
Ignacio Fernandez-Moncada, Daniel Robles-Maldonado, Pablo Castro, Karin Alegria, Robert Epp, Ivan Ruminot, Luis Felipe Barros
Summary: The acute rise in interstitial K+ levels during neural activity connects the energy demands of neurons with the metabolism of astrocytes. Elevated K+ levels stimulate aerobic glycolysis, inhibit mitochondrial respiration, and promote the release of lactate in astrocytes. The modulation of the glucose transporter GLUT1 by K+ allows astrocytes to maintain their glucose pool, support lactate production, and deliver glucose to active neurons.
Editorial Material
Endocrinology & Metabolism
L. F. Barros
Summary: Previously, it was believed that the energy cost of information processing was mainly attributed to neurons, with a minor fraction allocated to glial cells. However, there is compelling evidence that astrocytes also contribute significantly to this energy cost as they actively capture synaptic K+ using their Na+/K+ ATPase. This finding challenges the previous belief that astrocytes solely rely on Kir4.1 channels for K+ uptake. The implications of this discovery for reactive astrogliosis and brain diseases are discussed.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2022)
Article
Biochemistry & Molecular Biology
A. San Martin, R. Arce-Molina, C. Aburto, F. Baeza-Lehnert, L. F. Barros, Y. Contreras-Baeza, A. Pinilla, I Ruminot, D. Rauseo, P. Y. Sandoval
Summary: Metabolism research is undergoing a renaissance with the introduction of over 50 genetically-encoded fluorescent indicators (GEFIs) capable of monitoring metabolites with high resolution. These indicators allow monitoring of relative levels, concentrations, and fluxes in living systems, providing important tools for confirmation, rebuttal, and exploration.
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Article
Multidisciplinary Sciences
Patrick S. Hosford, Jack A. Wells, Shereen Nizari, Isabel N. Christie, Shefeeq M. Theparambil, Pablo A. Castro, Anna Hadjihambi, L. Felipe Barros, Ivan Ruminot, Mark F. Lythgoe, Alexander Gourine
Summary: The study indicates that CO2 plays a crucial role in regulating neurovascular coupling by mediating signaling between neurons and cerebral blood vessels to adjust local brain blood flow based on neuronal activity. The neurovascular coupling mechanism ensures an adequate energy supply for the brain to meet demands.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Daniel Cuervo-Zanatta, Tauqeerunnisa Syeda, Vicente Sanchez-Valle, Mariangel Irene-Fierro, Pablo Torres-Aguilar, Monica Adriana Torres-Ramos, Mineko Shibayama-Salas, Angelica Silva-Olivares, Lilia G. Noriega, Nimbe Torres, Armando R. Tovar, Ivan Ruminot, L. Felipe Barros, Jaime Garcia-Mena, Claudia Perez-Cruz
Summary: Fiber intake is associated with a lower risk for Alzheimer's disease in older adults. The neuroprotective effects of fiber intake may depend on the modulation of gut microbiota dysbiosis and specific actions of short-chain fatty acids in brain cells.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2023)
Article
Multidisciplinary Sciences
Vicente Medel, Nicolas Crossley, Ivana Gajardo, Eli Muller, L. Felipe Barros, James M. Shine, Jimena Sierralta
Summary: By analyzing gene expression data, we found that neuronal MCT2 lactate transporter is enriched in the cerebral cortex and negatively correlated with cortical thickness. MCT2 expression is associated with glucose utilization and brain function.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Physiology
L. F. Barros, I Ruminot, T. Sotelo-Hitschfeld, R. Lerchundi, I Fernandez-Moncada
Summary: Information processing in neurons requires significant metabolic resources, but neurons have limited energy stores. Metabolic recruitment is a tissue-level phenomenon where active neurons extract resources from their surroundings. This recruitment involves the release of K+ by neurons, the sensing of K+ by astrocytes, and the switch to a specific metabolic pathway. Glutamate, nitric oxide, and ammonium also act as recruiting signals in different domains.
ANNUAL REVIEW OF PHYSIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Camila Aburto, Alex Galaz, Angelo Bernier, Pamela Yohana Sandoval, Sebastian Holtheuer-Gallardo, Ivan Ruminot, Ignacio Soto-Ojeda, Helen Hertenstein, Johanna Aurelia Schweizer, Stefanie Schirmeier, Tammy Paulina Pastor, Gonzalo Antonio Mardones, Luis Felipe Barros, Alejandro San Martin
Summary: This study presents the development of a single-fluorophore indicator called CanlonicSF for lactate detection. The indicator offers high-resolution monitoring of lactate dynamics within cells, allowing for the development of high-throughput screening methods. The functionality of the indicator was demonstrated in living tissue of Drosophila melanogaster larvae, showing its potential application in vivo.
Article
Neurosciences
Vyara Todorova, Mia Fee Stauffacher, Luca Ravotto, Sarah Notzli, Duygu Karademir, Lynn J. A. Ebner, Cornelia Imsand, Luca Merolla, Stefanie. M. M. Hauck, Marijana Samardzija, Aiman. S. S. Saab, L. Felipe Barros, Bruno Weber, Christian Grimm
Summary: This study investigates the pathological mechanisms of photoreceptor (PR) degeneration during chronic activation of hypoxia-inducible factors (HIFs). The results show that PR cells have an exceptionally high glycolytic flux and the activation of HIFs slows down the cellular anabolism, leading to the shortening of rod outer segments before cell degeneration.
MOLECULAR NEURODEGENERATION
(2023)
Article
Neurosciences
L. F. Barros, I. Ruminot, P. Y. Sandoval, A. San Martin
Summary: Brain tissue metabolism can be studied at cellular and sub-cellular levels using genetically-encoded fluorescent indicators. These indicators provide information about relative levels, concentrations and fluxes of various metabolites. Although currently only a small fraction of the metabolome is accessible to fluorescent probes, there is optimism about future developments and their application in studying brain diseases.
NEUROBIOLOGY OF DISEASE
(2023)