Calcium‐Dependent Signaling in Astrocytes: Downstream Mechanisms and Implications for Cognition

Journal of Neurochemistry, Год журнала: 2025, Номер 169(2)

Опубликована: Фев. 1, 2025

Astrocytes are glial cells recognized for their diverse roles in regulating brain circuit structure and function. They can sense adapt to changes the microenvironment due unique structural biochemical properties. A key aspect of astrocytic function involves calcium (Ca2+)-dependent signaling, which serves as a fundamental mechanism interactions with neurons other brain. However, while significant progress has been made understanding spatio-temporal properties Ca2+ signals, downstream molecular pathways exact mechanisms through astrocytes decode these signals regulate homeostatic physiological processes remain poorly understood. To address this topic, we review here available literature on sources intracellular Ca2+, well its signaling pathways. We well-studied Ca2+-dependent exocytosis but draw attention additional that less understood are, most likely, highly influential many cellular functions. Finally, how is thought underlie neuron-astrocyte regions involved cognitive processing.

Язык: Английский

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The Glutamate/GABA‐Glutamine Cycle: Insights, Updates, and Advances

Journal of Neurochemistry, Год журнала: 2025, Номер 169(3)

Опубликована: Март 1, 2025

ABSTRACT Synaptic homeostasis of the principal neurotransmitters glutamate and GABA is tightly regulated by an intricate metabolic coupling between neurons astrocytes known as glutamate/GABA‐glutamine cycle. In this cycle, take up from synapse convert these into glutamine. Astrocytic glutamine subsequently transferred to neurons, serving precursor for neuronal synthesis. The cycle integrates multiple cellular processes, including neurotransmitter release, uptake, synthesis, metabolism. All processes are deeply interdependent closely coupled energy Astrocytes display highly active mitochondrial oxidative metabolism several unique features, glycogen storage pyruvate carboxylation, which essential sustain continuous release. However, new roles oligodendrocytes microglia in recycling emerging. Malfunction can lead severe synaptic disruptions may be implicated brain diseases. Here, I review central aspects recent advances highlight how functionally connected critical functions First, overview glutamate, GABA, transport provided relation recycling. Then, reviewed, with a special emphasis on glial cells. Finally, discuss aberrant linked neurodegeneration disease, focusing astrocyte dysfunction lipid emerging pathological mechanisms. Instead viewing individual biochemical more holistic integrative approach needed advance our understanding modulates function both health disease. image

Язык: Английский

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Hippocampal astrocytes induce sex-dimorphic effects on memory

Cell Reports, Год журнала: 2024, Номер 43(6), С. 114278 - 114278

Опубликована: Май 24, 2024

Astrocytic receptors influence cognitive function and can promote behavioral deficits in disease. These effects may vary based on variables such as biological sex, but it is not known if the of astrocytic are dependent sex. We leveraged vivo gene editing chemogenetics to examine roles spatial memory other processes. show that reductions metabotropic glutamate receptor 3 (mGluR3), main adults, impair females enhance males. Similarly, increases mGluR3 levels have sex-dependent females. manipulations also alter search strategies during recall a sex-specific manner. In addition, acute chemogenetic stimulation G

Язык: Английский

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Brain Metabolism in Health and Neurodegeneration: The Interplay Among Neurons and Astrocytes

Cells, Год журнала: 2024, Номер 13(20), С. 1714 - 1714

Опубликована: Окт. 17, 2024

The regulation of energy in the brain has garnered substantial attention recent years due to its significant implications various disorders and aging. brain's metabolism is a dynamic tightly regulated network that balances demand supply by engaging complementary molecular pathways. crosstalk among these pathways enables system switch preferred fuel source based on substrate availability, activity levels, cell state-related factors such as redox balance. Brain production relies multi-cellular cooperation continuously supplied from blood limited internal stores. Astrocytes, which interface with neurons vessels, play crucial role coordinating metabolic activity, their dysfunction can have detrimental effects health. This review characterizes major substrates (glucose, lactate, glycogen, ketones lipids) astrocyte health, focusing developments field.

Язык: Английский

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Identification of M4 muscarinic acetylcholine receptor expressing astrocytes that regulate locomotion and survival in murine prion disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

Abstract Whilst there has been much focus on the function of neuronally expressed members muscarinic acetylcholine receptor family (mAChR) less attention paid to expression profile and role five this (M 1 -M 5 mAChRs) in non-neuronal cells brain. Using genetically engineered mice we identify a previously unappreciated sub-population astrocytes expressing M 4 mAChR subtype. These are located various brain regions that include brainstem, hypothalamus and, most abundantly, cerebellum. Signalling proteomic analysis positive from cerebellum established functional subtype its regulation protein expression. Genetic ablation revealed specific locomotion behaviour. Importantly, context murine prion disease, model terminal neurodegeneration associated with profound neuroinflammation, observed significant expansion report experiments astrocyte detrimental effect late-stage disease. Together provide evidence play normal neurophysiology progression inflammatory neurodegenerative

Язык: Английский

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Neurodegenerative diseases and neuroinflammation-induced apoptosis

Open Life Sciences, Год журнала: 2025, Номер 20(1)

Опубликована: Янв. 1, 2025

Abstract Neuroinflammation represents a critical pathway in the brain for clearance of foreign bodies and maintenance homeostasis. When neuroinflammatory process is dysregulate, such as over-activation microglia, which results excessive accumulation free oxygen inflammatory factors brain, among other factors, it can lead to an imbalance homeostasis development various diseases. Recent research has indicated that numerous neurodegenerative diseases closely associated with neuroinflammation. The pathogenesis neuroinflammation intricate, involving alterations genes proteins, well activation inhibition signaling pathways. Furthermore, inflammation result neuronal cell apoptosis, further exacerbate extent disease. This article presents summary recent studies on relationship between apoptosis caused by aim identify link two provide new ideas targets exploring pathogenesis, prevention treatment

Язык: Английский

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Alzheimer’s Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models)

Brain Sciences, Год журнала: 2024, Номер 14(11), С. 1101 - 1101

Опубликована: Окт. 30, 2024

Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy difficult to prevent control when they develop. It has been known for many years these diseases pathogenic aspects in common. We highlight this review neuroglial cells (astroglia, oligodendroglia, microglia) play a vital role the origin, clinical-pathological development, course brain neurodegeneration. Moreover, we include new results T2D-AD mouse model (APP+PS1 mice on high-calorie diet) investigating.

Язык: Английский

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Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function

Glia, Год журнала: 2024, Номер 72(10), С. 1821 - 1839

Опубликована: Июнь 20, 2024

Abstract The neurometabolic disorder succinic semialdehyde dehydrogenase (SSADH) deficiency leads to great neurochemical imbalances and severe neurological manifestations. cause of the disease is loss function enzyme SSADH, leading impaired metabolism principal inhibitory neurotransmitter GABA. Despite known identity enzymatic deficit, underlying pathology SSADH remains unclear. To uncover new mechanisms disease, we performed an untargeted integrative analysis cerebral protein expression, functional metabolism, lipid composition in a genetic mouse model (ALDH5A1 knockout mice). Our proteomic revealed clear regional vulnerability, as alterations primarily manifested hippocampus cortex ALDH5A1 mice. These regions displayed aberrant expression proteins linked amino acid homeostasis, mitochondria, glial function, myelination. Stable isotope tracing acutely isolated brain slices demonstrated overall maintained oxidative glucose, but selective decrease astrocyte metabolic activity In contrast, elevated capacity glutamine was observed brain, which may serve neuronal compensation provision. addition reduced critical oligodendrocyte proteins, depletion myelin‐enriched sphingolipids found brains mice, suggesting degeneration myelin. Altogether, our study highlights that intimately pathology, targeting cells hold therapeutic potential this disease.

Язык: Английский

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Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 20, 2024

Abstract Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, targets, and disease relevance are not clear. Using site-selective suppressors genetic manipulations together with imaging multiomic profiling, we found that CIII is dominant source astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII-ROS was dependent on nuclear factor-κB (NF-κB) sodium-calcium exchanger (NCLX) caused oxidation select cysteines within immune metabolism-associated proteins linked neurological disease. amplified metabolomic pathology-associated transcriptional changes astrocytes, STAT3 activity as a major mediator, facilitated neuronal toxicity non-cell- autonomous manner. As proof-of-concept, suppression mice decreased dementia-linked tauopathy neuroimmune cascades extended lifespan. Our findings establish an important immunometabolic signal transducer tractable therapeutic target neurodegenerative

Язык: Английский

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The chromatin conformation landscape of Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 13, 2024

ABSTRACT We have been investigating epigenetic alterations in the brain during human aging and Alzheimer’s disease (AD), evidence for histone acetylation both protecting epigenome driving AD. Here we extend our studies to chromatin architecture via looping studies, with binding of key proteins required looping: CTCF RAD21. detected changes RAD21 levels localization, finding major AD compared fewer healthy aging. In study 3D genome conformation changes, identified stable topological associating domains (TADs) Old AD; contrast, AD, there is loss interaction at genomic sites/loops within TADs, likely reflecting CTCF. genes potential transcription factor loops that are lost addition, found enrichment peak losses eQTLs, suggesting architectural dysfunction has a role Alzheimer’s. Functional experiments lowering homologues several Drosophila model Aβ42 toxicity exacerbate neurodegeneration. Taken together, these data indicate functional protections occur normal

Язык: Английский

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