About

Alfonso Araque is a professor in the Department of Neuroscience at the University of Minnesota. His research focuses on the mechanisms, properties, and physiological consequences of communication between neurons and astrocytes. His work aims to understand how this communication affects physiological and pathological aspects of brain function. His team investigates how astrocytes respond to neuronal activity, control neuronal activity, and influence synaptic transmission and plasticity, contributing to neural network function. His previous work provided the first demonstration of regulation of synaptic transmission by astrocytes and defined the Tripartite Synapse concept, which views astrocytes as integral elements of synapses exchanging information signals with neurons. His recent contributions include demonstrating astrocytes' integrative properties for synaptic information processing, their regulation of synaptic transmission at single synapses, and their involvement in endocannabinoid signaling. He has also designed artificial AstroNeuronal networks, showing that artificial astrocytes can improve network performance, and demonstrated astrocyte-mediated synaptic plasticity in vivo and astrocyte-neuron signaling in human brain tissue. His current research investigates the cellular mechanisms and physio-pathological consequences of astrocyte-neuron interactions across different brain areas, testing the hypothesis that brain function results from the operation of AstroNeuronal networks established by the coordinated activity of astrocytes and neurons, and exploring how alterations in these networks contribute to brain diseases.

Research topics

• Biology
• Neuroscience
• Cell biology
• Medicine
• Psychology
• Chemistry
• Biochemistry
• Internal medicine
• Immunology

Selected publications

• Complement 3a Receptor mediates high fat diet induced hypothalamic accumulation of lipid associated microglia to regulate neuroinflammation and obesity

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-22

  articleOpen access

  Microglia, the resident macrophages of the central nervous system, are recognized for their heterogeneity and integral role in brain function and diseases. In the context of high fat diet (HFD) feeding and obesity, microglia become overactive, acquiring a prevailing lipid associated microglial phenotype (also known as LAM). Yet, how microgliosis is induced and regulated remains unclear. Here we report a key role for the Complement 3a Receptor (C3aR), on HFD-induced hypothalamic gliosis and weight gain in mice. HFD consumption leads to elevated microglial expression of C3aR, which parallels widespread accumulation of reactive microglia, selectively in the hypothalamus. Conditional microglial C3aR deletion protects mice from HFD-induced hypothalamic reactive microgliosis. C3aR deletion or pharmacological antagonism opposes HFD-induced weight gain in male but not female mice. Mechanistically, we demonstrated that C3aR is essential for lipid-induced lipid droplet formation, and acquisition of a LAM molecular signature. In summary, we uncovered a previously unknown role for C3aR in the acquisition of a LAM signature driving diet-induced gliosis, identifying this receptor as a new viable therapeutic candidate for conditions associated with hypothalamic neuroinflammation.

  PublisherDOI

• Astrocyte-neuron signaling in aging

  Ageing & Longevity · 2025-02-27 · 1 citations

  articleOpen access

  Rapid increases in the aging population present a critical challenge to global societies, with a major concern being cognitive decline and brain aging. While neuroscientific research has traditionally focused on neurons, the role of astrocytes in aging is of recent interest but remains underexplored. Astrocytes, the homeostatic cells on the central nervous system, play essential roles in synaptic regulation, neurotransmitter clearance, neuronal support, and homeostasis. Recent studies indicate that astrocytes undergo significant morphological and functional changes during aging, affecting calcium signaling, gap junction communication, and homeostatic functions. Altered calcium dynamics in aged astrocytes impact gliotransmission, synaptic transmission, and plasticity, with evidence of dysregulated intracellular calcium sequestration and reduced astrocytic network connectivity. Aging modifies key intrinsic astrocytic properties, including connexins, aquaporins, potassium channels, and glutamate transporters, which are crucial for maintaining astrocyte networks, synaptic stability, and preventing excitotoxicity. These functional consequences suggest that astrocytes play an integral role on age-related cognitive decline. An increasing number of research studies have begun to explore therapeutic strategies to target astrocytes to mitigate brain aging or reverse age-related decline. Approaches such as utilizing pharmacological agents such as caloric restriction mimetics and activators of purinergic and metabotropic glutamate receptors have demonstrated potential in restoring astrocyte function and improving cognitive outcomes. Enhancing astrocytic Ca²⁺ signaling, adrenergic modulation, restoring aquaporin-4 polarization, and activating the Nrf2 pathway have also emerged as promising intervention targets. Understanding astrocyte-neuron interactions in aging and developing astrocyte-targeted therapies could pave the way for novel treatments to preserve cognitive function and combat neurodegenerative diseases.

  PublisherOA PDFDOI

• Protein kinase CK2α’ as a dual modulator of immune signaling and synaptic dysfunction in Tauopathy

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-25

  preprintOpen access

  Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein Kinase CK2 has been previously associated with different aspects of tau pathology but genetic evidence for the contribution of CK2 to tauopathy remained lacking. Here, we show CK2α', one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. We found that CK2α' expression is elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using genetic haploinsufficiency in PS19 mice, we demonstrated that reduced CK2α' levels significantly decrease phosphorylated tau and total tau burden in the hippocampus and cortex. CK2α' depletion also attenuated microglial activation, pro-inflammatory cytokine production, and microglia synaptic engulfment, enhanced synaptic gene expression, synaptic density, and LTP. Importantly, CK2α' depletion rescued cognitive deficits assessed in the Barnes maze. These effects appear to be mediated through both neuronal and glial functions and may involve CK2α'-dependent modulation of tau-associated phosphorylation and neuroinflammatory and immune signaling pathways.

  PublisherOA PDFDOI

• The Duality of Astrocyte Neuromodulation: Astrocytes Sense Neuromodulators and Are Neuromodulators

  Journal of Neurochemistry · 2025-04-01 · 10 citations

  reviewOpen accessSenior authorCorresponding

  Neuromodulation encompasses different processes that regulate neuronal and network function. Classical neuromodulators originating from long-range nuclei, such as acetylcholine, norepinephrine, or dopamine, act with a slower time course and wider spatial range than fast synaptic transmission and action potential firing. Accumulating evidence in vivo indicates that astrocytes, which are known to actively participate in synaptic function at tripartite synapses, are also involved in neuromodulatory processes. The present article reviews recent findings obtained in vivo indicating that astrocytes express receptors for neuromodulators that elevate their internal calcium and stimulate the release of gliotransmitters, which regulate synaptic and network function, and hence mediate, at least partially, the effects of neuromodulators. In addition, we propose that astrocytes act in local support of neuromodulators by spatially and temporally integrating neuronal and neuromodulatory signals to regulate neural network function. The presence of astrocyte-neuron hysteresis loops suggests astrocyte-neuron interaction at tripartite synapses scales up to astrocyte-neuronal networks that modulate neural network function. We finally propose that astrocytes sense the environmental conditions, including neuromodulators and network function states, and provide homeostatic control that maximizes the dynamic range of neural network activity. In summary, we propose that astrocytes are critical in mediating the effects of neuromodulators, and they also act as neuromodulators to provide neural network homeostasis thus optimizing information processing in the brain. Hence, astrocytes sense ongoing neuronal activity along with neuromodulators and, acting as neuromodulators, inform the neurons about the state of the internal system and the external world.

  PublisherOA PDFDOI

• Protein kinase CK2α’ as a dual modulator of neuroimmune signaling and synaptic dysfunction in Tauopathy

  Research Square · 2025-08-07

  preprintOpen access
  PublisherOA PDFDOI

• Estradiol Mediates Astrocyte-Neuron Communication in the Hippocampus

  Molecular Neurobiology · 2025-04-10 · 8 citations

  articleOpen accessSenior author

  Accumulating evidence has revealed the existence of functional astrocyte-neuron communication based on the ability of astrocytes to respond to neurotransmitters and release gliotransmitters. However, little is known about how other signaling molecules, such as hormones, impact astrocyte function. Estradiol (E2) is an important hormone known to regulate neuronal activity, synaptic transmission, plasticity, and animal behavior. However, whether E2 specifically signals to astrocytes in situ and the functional consequences on astrocyte-neuron communication remain unknown. Therefore, we investigated the impact of estradiol on astrocyte activity and astrocyte-neuron communication in the mouse hippocampus. Using an RNAscope approach, we determined that estrogen receptors (ERα and ERβ) are expressed in astrocytes in both female and male mice. In both sexes, confocal imaging of hippocampal slices determined that astrocytes respond to locally applied E2 with calcium elevations. In pyramidal neurons, slow inward currents (SICs) are mediated by the activation of extrasynaptic NMDA receptors and indicate gliotransmission. Electrophysiological recordings of hippocampal neurons determined that E2 increases the frequency, but not the amplitude, of SICs. We also recorded excitatory synaptic transmission evoked by Schaffer collateral stimulation. Here, only in females, did E2 produce a reduction in excitatory synaptic transmission. The E2-induced effects on the astrocyte calcium signal and gliotransmission were prevented by the broad estrogen receptor antagonist ICI 182,780. Taken together, these results demonstrate the existence of estradiol-mediated astrocyte-neuron communication in both female and male mice. They reveal that E2 can signal to astrocytes and, through this signaling, E2 may regulate neuronal activity and synaptic transmission.

  PublisherOA PDFDOI

• Astrocytes Mediate Psychostimulant‐Induced Alterations of Spike‐Timing Dependent Synaptic Plasticity

  Glia · 2025-01-13 · 3 citations

  articleOpen access

  ABSTRACT At cellular and circuit levels, drug addiction is considered a dysregulation of synaptic plasticity. In addition, dysfunction of the glutamate transporter 1 (GLT‐1) in the nucleus accumbens (NAc) has also been proposed as a mechanism underlying drug addiction. However, the cellular and synaptic impact of GLT‐1 alterations in the NAc remain unclear. Here we show in the NAc that 10 days withdraw after 5 days treatment with cocaine or amphetamine decreases GLT‐1 expression in astrocytes, which results in the prolongation of the excitatory postsynaptic potential (EPSP) decay kinetics in D1 receptor‐containing medium spiny neurons (D1R‐MSNs). Using the spike timing dependent plasticity (STDP) paradigm, we found that enlargement of EPSP duration results in switching the LTP elicited in control animals to LTD in psychostimulant‐treated mice. In contrast to D1‐MSNs, D2‐MSNs did not display changes in EPSP kinetics and synaptic plasticity. Notably, the psychostimulant‐induced synaptic transmission and synaptic plasticity effects were absent in IP3R2 −/− mice, which lack astrocyte calcium signal, but were mimicked by the selective astrocytes stimulation with DREADDs. Finally, ceftriaxone, which upregulates GLT‐1, restored normal GLT‐1 function, EPSP kinetics, and synaptic plasticity in psychostimulant‐treated mice. Therefore, we propose that cocaine and amphetamine increase dopaminergic levels in the NAc, which stimulates astrocytes and downregulates the GLT‐1. The decreased GLT‐1 function prolonged the EPSP kinetics, leading to the modulation of the STDP, transforming the LTP observed in control animals into LTD in psychostimulant‐treated mice. Present work reveals a novel mechanism underlying the synaptic plasticity changes induced by these drugs of abuse.

  PublisherOA PDFDOI

• Astrocytic Glucose Sensing Drives Synaptic Depression under Metabolic Stress

  Aging and Disease · 2025-01-01 · 1 citations

  articleOpen access

  Glucose is the primary energy source for the brain, and its continuous supply is essential for neuronal function. Astrocytes play a pivotal role in brain energy metabolism by mediating glucose uptake, sensing metabolic fluctuations, and modulating synaptic activity. However, astrocyte responses to transient glucose deprivation remain incompletely understood. Here, we demonstrate that astrocytic glucose uptake is crucial for network adaptation to metabolic stress. Using electrophysiology and calcium imaging approaches, we show that glucose deprivation depresses hippocampal synaptic transmission through an astrocyte-dependent mechanism that involves decreased glucose transporter 1 (GLUT1)-facilitated extracellular glucose uptake, intracellular calcium elevations, and ATP/adenosine-mediated signaling, which leads to excitatory neurotransmission depression via A1 receptors. Moreover, astrocyte-specific GLUT1 depletion prevents astrocytic responses to glucose deprivation and precludes the effects of glucose deprivation on synaptic transmission, thereby indicating that GLUT1-dependent glucose uptake is involved in astrocyte-mediated modulation of synaptic function. These findings extend the concept of astrocytic metabolic regulation beyond regions canonically classified as glucose-sensing and establish astrocytes as key integrators of energy availability and synaptic function. Our study provides new insights into the role of astrocytes in brain energy homeostasis and identifies potential therapeutic targets for metabolic disorders affecting the nervous system.

  PublisherOA PDFDOI

• Author response for "The Duality of Astrocyte Neuromodulation: Astrocytes Sense Neuromodulators and Are Neuromodulators"

  2025-03-15

  peer-reviewSenior author
  PublisherDOI

• A spatial threshold for astrocyte calcium surge

  eLife · 2024-11-18 · 3 citations

  preprintOpen accessSenior author

  Abstract Astrocytes are active cells involved in brain function through the bidirectional communication with neurons, in which the astrocyte calcium signal plays a crucial role. Synaptically-evoked calcium increases can be localized to independent subcellular domains or expand to the entire cell, i.e., calcium surge. In turn, astrocytes may regulate individual synapses by calcium-dependent release of gliotransmitters. Because a single astrocyte may contact ∼100,000 synapses, the control of the intracellular calcium signal propagation may have relevant consequences on brain function by regulating the spatial range of astrocyte neuromodulation of synapses. Yet, the properties governing the spatial dynamics of the astrocyte calcium signal remains poorly defined. Imaging subcellular responses of cortical astrocytes to sensory stimulation in mice, we show that sensory-evoked astrocyte calcium responses originated and remained localized in domains of the astrocytic arborization, but eventually propagated to the entire cell if a spatial threshold of >23% of the arborization being activated was surpassed. Using transgenic IP3R2-/- mice, we found that type-2 IP3 receptors were necessary for the generation of the astrocyte calcium surge. We finally show using in situ electrophysiological recordings that the spatial threshold of the astrocyte calcium signal consequently determined the gliotransmitter release. Present results reveal a fundamental property of astrocyte calcium physiology, i.e., a spatial threshold for the astrocyte intracellular calcium signal propagation, which depends on astrocyte intrinsic properties and governs the astrocyte integration of local synaptic activity and the subsequent neuromodulation.

  PublisherDOI

Recent grants

• Astrocyte-neuron interaction in behavior driven by striatal information processing

  NIH · $1.8M · 2016–2021

• Astrocyte activity in amygdala-related fear conditioned behaviors

  NIH · $2.3M · 2020–2026

• Role of astrocytes in dopamine signaling and psychostimulant effects

  NIH · $1.8M · 2019–2025

• Tau-dependent cognitive deficits in alpha-synucleinopathies

  NIH · $2.8M · 2018–2025

Frequent coauthors

• Ying Zhang

  82 shared

• Gertrudis Perea

  Instituto Cajal

  70 shared

• Washington Buño

  Instituto Cajal

  48 shared

• Marta Navarrete

  Instituto Cajal

  48 shared

• E. Martin

  Instituto Cajal

  42 shared

• Paulo Kofuji

  University of Minnesota

  32 shared

• Juan Aguilar

  Hospital Nacional de Parapléjicos

  28 shared

• Andrés M. Baraibar

  28 shared

Labs

• Institute for Translational NeurosciencePI

Education

• PhD

  Universidad Complutense de Madrid

  1993