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Papers by cendra agulhon

bioRxiv (Cold Spring Harbor Laboratory), Apr 20, 2024

bioRxiv (Cold Spring Harbor Laboratory), Apr 19, 2024

Physiology News, Sep 1, 2008

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2013

The Journal of Physiology, Sep 1, 2007

Astrocytes comprise approximately half of the volume of the adult mammalian brain and are the pri... more Astrocytes comprise approximately half of the volume of the adult mammalian brain and are the primary neuronal structural and trophic supportive elements. Astrocytes are organized into distinct nonoverlapping domains and extend elaborate and dense fine processes that interact intimately with synapses and cerebrovasculature. The recognition in the mid 1990s that astrocytes undergo elevations in intracellular calcium concentration following activation of G protein-coupled receptors by synaptically released neurotransmitters demonstrated not only that astrocytes display a form of excitability but also that astrocytes may be active participants in brain information processing. The roles that astrocytic calcium elevations play in neurophysiology and especially in modulation of neuronal activity have been intensely researched in recent years. This review will summarize the current understanding of the function of astrocytic calcium signaling in neurophysiological processes and discuss are...

Proceedings of the National Academy of Sciences of the United States of America, Jun 5, 2001

European Journal of Neuroscience, Feb 25, 2005

Measurements of local Ca2+ signalling at different developmental stages and/or in specific cell t... more Measurements of local Ca2+ signalling at different developmental stages and/or in specific cell types is important for understanding aspects of brain functioning. The use of light excitation in fluorescence imaging can cause phototoxicity, photobleaching and auto-fluorescence. In contrast, bioluminescence does not require the input of radiative energy and can therefore be measured over long periods, with very high temporal resolution. Aequorin is a genetically encoded Ca(2+)-sensitive bioluminescent protein, however, its low quantum yield prevents dynamic measurements of Ca2+ responses in single cells. To overcome this limitation, we recently reported the bi-functional Ca2+ reporter gene, GFP-aequorin (GA), which was developed specifically to improve the light output and stability of aequorin chimeras [V. Baubet, et al., (2000) PNAS, 97, 7260-7265]. In the current study, we have genetically targeted GA to different microdomains important in synaptic transmission, including to the mitochondrial matrix, endoplasmic reticulum, synaptic vesicles and to the postsynaptic density. We demonstrate that these reporters enable 'real-time' measurements of subcellular Ca2+ changes in single mammalian neurons using bioluminescence. The high signal-to-noise ratio of these reporters is also important in that it affords the visualization of Ca2+ dynamics in cell-cell communication in neuronal cultures and tissue slices. Further, we demonstrate the utility of this approach in ex-vivo preparations of mammalian retina, a paradigm in which external light input should be controlled. This represents a novel molecular imaging approach for non-invasive monitoring of local Ca2+ dynamics and cellular communication in tissue or whole animal studies.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2008

Page 1. Chapter 14 Molecular Approaches for Studying Astrocytes Todd Fiacco , Kristi Casper , Eli... more Page 1. Chapter 14 Molecular Approaches for Studying Astrocytes Todd Fiacco , Kristi Casper , Elizabeth Sweger , Cendra Agulhon , Sarah Taves , Suzanne Kurtzer-Minton , and Ken D. McCarthy 14.1 Introduction In the year ...

Science, 2019

An inhibitor causes neuronal excitation Glycine is thought to be primarily an inhibitory neurotra... more An inhibitor causes neuronal excitation Glycine is thought to be primarily an inhibitory neurotransmitter. However, it also acts as a coagonist on excitatory N -methyl-D-aspartate (NMDA) receptors. Otsu et al. examined the function of the NMDA receptor subunit combination GluN1/GluN3A in the medial habenula (MHb) of adult mice. This NMDA receptor subunit combination in MHb neurons is activated by glycine released from astrocytes. Activation of GluN1/GluN3A NMDA receptors causes depolarization and increased spiking of MHb neurons. Reducing GluN3A receptor subunit levels in the MHb blocks conditioned place aversion. Science , this issue p. 250

Scientific Reports, 2019

The cochlea is innervated by type I and type II afferent neurons. Type I afferents are myelinated... more The cochlea is innervated by type I and type II afferent neurons. Type I afferents are myelinated, larger diameter neurons that send a single dendrite to contact a single inner hair cell, whereas unmyelinated type II afferents are fewer in number and receive input from many outer hair cells. This strikingly differentiated innervation pattern strongly suggests specialized functions. Those functions could be investigated with specific genetic markers that enable labeling and manipulating each afferent class without significantly affecting the other. Here three mouse models were characterized and tested for specific labeling of either type I or type II cochlear afferents. Nos1CreER mice showed selective labeling of type I afferent fibers, Slc6a4-GFP mice labeled type II fibers with a slight preference for the apical cochlea, and Drd2-Cre mice selectively labeled type II afferent neurons nearer the cochlear base. In conjunction with the Th2A-CreER and CGRPα-EGFP lines described previous...

Scientific Reports, 2017

The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; h... more The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve an...

Neuroreport, Jan 2, 1999

The aim of this study was to determine the regional distribution in situ of the mRNA for the alph... more The aim of this study was to determine the regional distribution in situ of the mRNA for the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor in human fetal brain. We found high levels of alpha 7 gene expression in nuclei that receive sensory information, such as those of the neocortex and hippocampus, the thalamic nuclei, the reticular thalamic nucleus, the pontine nuclei and the superior olive complex. These data support a possible regulatory function for alpha 7-containing receptors in sensory processing, which may be involved in the pathological physiology of schizophrenia and autism. Early alpha 7 gene expression is also consistent with a morphogenetic role for alpha 7 receptors in central nervous system development.

Astrocytes in (Patho)Physiology of the Nervous System, 2008

Page 1. Chapter 14 Molecular Approaches for Studying Astrocytes Todd Fiacco , Kristi Casper , Eli... more Page 1. Chapter 14 Molecular Approaches for Studying Astrocytes Todd Fiacco , Kristi Casper , Elizabeth Sweger , Cendra Agulhon , Sarah Taves , Suzanne Kurtzer-Minton , and Ken D. McCarthy 14.1 Introduction In the year ...

Frontiers in Cellular Neuroscience, 2013

Gray matter protoplasmic astrocytes extend very thin processes and establish close contacts with ... more Gray matter protoplasmic astrocytes extend very thin processes and establish close contacts with synapses. It has been suggested that the release of neuroactive gliotransmitters at the tripartite synapse contributes to information processing. However, the concept of calcium (Ca 2+)-dependent gliotransmitter release from astrocytes, and the release mechanisms are being debated. Studying astrocytes in their natural environment is challenging because: (i) astrocytes are electrically silent; (ii) astrocytes and neurons express an overlapping repertoire of transmembrane receptors; (iii) the size of astrocyte processes in contact with synapses are below the resolution of confocal and twophoton microscopes (iv) bulk-loading techniques using fluorescent Ca 2+ indicators lack cellular specificity. In this review, we will discuss some limitations of conventional methodologies and highlight the interest of novel tools and approaches for studying gliotransmission. Genetically encoded Ca 2+ indicators (GECIs), light-gated channels, and exogenous receptors are being developed to selectively read out and stimulate astrocyte activity. Our review discusses emerging perspectives on: (i) the complexity of astrocyte Ca 2+ signaling revealed by GECIs; (ii) new pharmacogenetic and optogenetic approaches to activate specific Ca 2+ signaling pathways in astrocytes; (iii) classical and new techniques to monitor vesicle fusion in cultured astrocytes; (iv) possible strategies to express specifically reporter genes in astrocytes.

Frontiers in Cellular Neuroscience, 2013

Astrocytes are a predominant glial cell type in the nervous systems, and are becoming recognized ... more Astrocytes are a predominant glial cell type in the nervous systems, and are becoming recognized as important mediators of normal brain function as well as neurodevelopmental, neurological, and neurodegenerative brain diseases. Although numerous potential mechanisms have been proposed to explain the role of astrocytes in the normal and diseased brain, research into the physiological relevance of these mechanisms in vivo is just beginning. In this review, we will summarize recent developments in innovative and powerful molecular approaches, including knockout mouse models, transgenic mouse models, and astrocytetargeted gene transfer/expression, which have led to advances in understanding astrocyte biology in vivo that were heretofore inaccessible to experimentation. We will examine the recently improved understanding of the roles of astrocytes-with an emphasis on astrocyte signaling-in the context of both the healthy and diseased brain, discuss areas where the role of astrocytes remains debated, and suggest new research directions.

Open Life Sciences, 2008

Neurotrophic factors have been widely suggested as a treatment for multiple diseases including mo... more Neurotrophic factors have been widely suggested as a treatment for multiple diseases including motorneuron pathologies, like Amyotrophic Lateral Sclerosis. However, clinical trials in which growth factors have been systematically administered to Amyotrophic Lateral Sclerosis patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. A possible strategy is the use of the atoxic C fragment of the tetanus toxin as a neurotrophic factor carrier to the motorneurons. The activity of trophic factors should be tested because their genetic fusion to proteins could alter their folding and conformation, thus undermining their neuroprotective properties. For this purpose, in this paper we explored the Brain Derived Neurotrophic Factor (BDNF) activity maintenance after genetic fusion with the C fragment of the tetanus toxin. We demonstrated that BDNF fused with the C fragment of the tetanus toxin induces the neuronal surv...

The Journal of Physiology, 2013

Key points The activation of glial Gq protein‐coupled receptor (Gq‐GPCR) signalling cascades broa... more Key points The activation of glial Gq protein‐coupled receptor (Gq‐GPCR) signalling cascades broadly activates the autonomic nervous system The activation of glial Gq‐GPCR signalling cascades affects activity‐related behaviour. : Glial fibrillary acidic protein (GFAP)‐expressing cells (GFAP+ glial cells) are the predominant cell type in the central and peripheral nervous systems. Our understanding of the role of GFAP+ glial cells and their signalling systems in vivo is limited due to our inability to manipulate these cells and their receptors in a cell type‐specific and non‐invasive manner. To circumvent this limitation, we developed a transgenic mouse line (GFAP‐hM3Dq mice) that expresses an engineered Gq protein‐coupled receptor (Gq‐GPCR) known as hM3Dq DREADD (designer receptor exclusively activated by designer drug) selectively in GFAP+ glial cells. The hM3Dq receptor is activated solely by a pharmacologically inert, but bioavailable, ligand (clozapine‐N‐oxide; CNO), while bein...

bioRxiv (Cold Spring Harbor Laboratory), Apr 20, 2024

bioRxiv (Cold Spring Harbor Laboratory), Apr 19, 2024

Physiology News, Sep 1, 2008

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2013

The Journal of Physiology, Sep 1, 2007

Astrocytes comprise approximately half of the volume of the adult mammalian brain and are the pri... more Astrocytes comprise approximately half of the volume of the adult mammalian brain and are the primary neuronal structural and trophic supportive elements. Astrocytes are organized into distinct nonoverlapping domains and extend elaborate and dense fine processes that interact intimately with synapses and cerebrovasculature. The recognition in the mid 1990s that astrocytes undergo elevations in intracellular calcium concentration following activation of G protein-coupled receptors by synaptically released neurotransmitters demonstrated not only that astrocytes display a form of excitability but also that astrocytes may be active participants in brain information processing. The roles that astrocytic calcium elevations play in neurophysiology and especially in modulation of neuronal activity have been intensely researched in recent years. This review will summarize the current understanding of the function of astrocytic calcium signaling in neurophysiological processes and discuss are...

Proceedings of the National Academy of Sciences of the United States of America, Jun 5, 2001

European Journal of Neuroscience, Feb 25, 2005

Measurements of local Ca2+ signalling at different developmental stages and/or in specific cell t... more Measurements of local Ca2+ signalling at different developmental stages and/or in specific cell types is important for understanding aspects of brain functioning. The use of light excitation in fluorescence imaging can cause phototoxicity, photobleaching and auto-fluorescence. In contrast, bioluminescence does not require the input of radiative energy and can therefore be measured over long periods, with very high temporal resolution. Aequorin is a genetically encoded Ca(2+)-sensitive bioluminescent protein, however, its low quantum yield prevents dynamic measurements of Ca2+ responses in single cells. To overcome this limitation, we recently reported the bi-functional Ca2+ reporter gene, GFP-aequorin (GA), which was developed specifically to improve the light output and stability of aequorin chimeras [V. Baubet, et al., (2000) PNAS, 97, 7260-7265]. In the current study, we have genetically targeted GA to different microdomains important in synaptic transmission, including to the mitochondrial matrix, endoplasmic reticulum, synaptic vesicles and to the postsynaptic density. We demonstrate that these reporters enable 'real-time' measurements of subcellular Ca2+ changes in single mammalian neurons using bioluminescence. The high signal-to-noise ratio of these reporters is also important in that it affords the visualization of Ca2+ dynamics in cell-cell communication in neuronal cultures and tissue slices. Further, we demonstrate the utility of this approach in ex-vivo preparations of mammalian retina, a paradigm in which external light input should be controlled. This represents a novel molecular imaging approach for non-invasive monitoring of local Ca2+ dynamics and cellular communication in tissue or whole animal studies.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2008

Page 1. Chapter 14 Molecular Approaches for Studying Astrocytes Todd Fiacco , Kristi Casper , Eli... more Page 1. Chapter 14 Molecular Approaches for Studying Astrocytes Todd Fiacco , Kristi Casper , Elizabeth Sweger , Cendra Agulhon , Sarah Taves , Suzanne Kurtzer-Minton , and Ken D. McCarthy 14.1 Introduction In the year ...

Science, 2019

An inhibitor causes neuronal excitation Glycine is thought to be primarily an inhibitory neurotra... more An inhibitor causes neuronal excitation Glycine is thought to be primarily an inhibitory neurotransmitter. However, it also acts as a coagonist on excitatory N -methyl-D-aspartate (NMDA) receptors. Otsu et al. examined the function of the NMDA receptor subunit combination GluN1/GluN3A in the medial habenula (MHb) of adult mice. This NMDA receptor subunit combination in MHb neurons is activated by glycine released from astrocytes. Activation of GluN1/GluN3A NMDA receptors causes depolarization and increased spiking of MHb neurons. Reducing GluN3A receptor subunit levels in the MHb blocks conditioned place aversion. Science , this issue p. 250

Scientific Reports, 2019

The cochlea is innervated by type I and type II afferent neurons. Type I afferents are myelinated... more The cochlea is innervated by type I and type II afferent neurons. Type I afferents are myelinated, larger diameter neurons that send a single dendrite to contact a single inner hair cell, whereas unmyelinated type II afferents are fewer in number and receive input from many outer hair cells. This strikingly differentiated innervation pattern strongly suggests specialized functions. Those functions could be investigated with specific genetic markers that enable labeling and manipulating each afferent class without significantly affecting the other. Here three mouse models were characterized and tested for specific labeling of either type I or type II cochlear afferents. Nos1CreER mice showed selective labeling of type I afferent fibers, Slc6a4-GFP mice labeled type II fibers with a slight preference for the apical cochlea, and Drd2-Cre mice selectively labeled type II afferent neurons nearer the cochlear base. In conjunction with the Th2A-CreER and CGRPα-EGFP lines described previous...

Scientific Reports, 2017

The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; h... more The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve an...

Neuroreport, Jan 2, 1999

The aim of this study was to determine the regional distribution in situ of the mRNA for the alph... more The aim of this study was to determine the regional distribution in situ of the mRNA for the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor in human fetal brain. We found high levels of alpha 7 gene expression in nuclei that receive sensory information, such as those of the neocortex and hippocampus, the thalamic nuclei, the reticular thalamic nucleus, the pontine nuclei and the superior olive complex. These data support a possible regulatory function for alpha 7-containing receptors in sensory processing, which may be involved in the pathological physiology of schizophrenia and autism. Early alpha 7 gene expression is also consistent with a morphogenetic role for alpha 7 receptors in central nervous system development.

Astrocytes in (Patho)Physiology of the Nervous System, 2008

Page 1. Chapter 14 Molecular Approaches for Studying Astrocytes Todd Fiacco , Kristi Casper , Eli... more Page 1. Chapter 14 Molecular Approaches for Studying Astrocytes Todd Fiacco , Kristi Casper , Elizabeth Sweger , Cendra Agulhon , Sarah Taves , Suzanne Kurtzer-Minton , and Ken D. McCarthy 14.1 Introduction In the year ...

Frontiers in Cellular Neuroscience, 2013

Gray matter protoplasmic astrocytes extend very thin processes and establish close contacts with ... more Gray matter protoplasmic astrocytes extend very thin processes and establish close contacts with synapses. It has been suggested that the release of neuroactive gliotransmitters at the tripartite synapse contributes to information processing. However, the concept of calcium (Ca 2+)-dependent gliotransmitter release from astrocytes, and the release mechanisms are being debated. Studying astrocytes in their natural environment is challenging because: (i) astrocytes are electrically silent; (ii) astrocytes and neurons express an overlapping repertoire of transmembrane receptors; (iii) the size of astrocyte processes in contact with synapses are below the resolution of confocal and twophoton microscopes (iv) bulk-loading techniques using fluorescent Ca 2+ indicators lack cellular specificity. In this review, we will discuss some limitations of conventional methodologies and highlight the interest of novel tools and approaches for studying gliotransmission. Genetically encoded Ca 2+ indicators (GECIs), light-gated channels, and exogenous receptors are being developed to selectively read out and stimulate astrocyte activity. Our review discusses emerging perspectives on: (i) the complexity of astrocyte Ca 2+ signaling revealed by GECIs; (ii) new pharmacogenetic and optogenetic approaches to activate specific Ca 2+ signaling pathways in astrocytes; (iii) classical and new techniques to monitor vesicle fusion in cultured astrocytes; (iv) possible strategies to express specifically reporter genes in astrocytes.

Frontiers in Cellular Neuroscience, 2013

Astrocytes are a predominant glial cell type in the nervous systems, and are becoming recognized ... more Astrocytes are a predominant glial cell type in the nervous systems, and are becoming recognized as important mediators of normal brain function as well as neurodevelopmental, neurological, and neurodegenerative brain diseases. Although numerous potential mechanisms have been proposed to explain the role of astrocytes in the normal and diseased brain, research into the physiological relevance of these mechanisms in vivo is just beginning. In this review, we will summarize recent developments in innovative and powerful molecular approaches, including knockout mouse models, transgenic mouse models, and astrocytetargeted gene transfer/expression, which have led to advances in understanding astrocyte biology in vivo that were heretofore inaccessible to experimentation. We will examine the recently improved understanding of the roles of astrocytes-with an emphasis on astrocyte signaling-in the context of both the healthy and diseased brain, discuss areas where the role of astrocytes remains debated, and suggest new research directions.

Open Life Sciences, 2008

Neurotrophic factors have been widely suggested as a treatment for multiple diseases including mo... more Neurotrophic factors have been widely suggested as a treatment for multiple diseases including motorneuron pathologies, like Amyotrophic Lateral Sclerosis. However, clinical trials in which growth factors have been systematically administered to Amyotrophic Lateral Sclerosis patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. A possible strategy is the use of the atoxic C fragment of the tetanus toxin as a neurotrophic factor carrier to the motorneurons. The activity of trophic factors should be tested because their genetic fusion to proteins could alter their folding and conformation, thus undermining their neuroprotective properties. For this purpose, in this paper we explored the Brain Derived Neurotrophic Factor (BDNF) activity maintenance after genetic fusion with the C fragment of the tetanus toxin. We demonstrated that BDNF fused with the C fragment of the tetanus toxin induces the neuronal surv...

The Journal of Physiology, 2013

Key points The activation of glial Gq protein‐coupled receptor (Gq‐GPCR) signalling cascades broa... more Key points The activation of glial Gq protein‐coupled receptor (Gq‐GPCR) signalling cascades broadly activates the autonomic nervous system The activation of glial Gq‐GPCR signalling cascades affects activity‐related behaviour. : Glial fibrillary acidic protein (GFAP)‐expressing cells (GFAP+ glial cells) are the predominant cell type in the central and peripheral nervous systems. Our understanding of the role of GFAP+ glial cells and their signalling systems in vivo is limited due to our inability to manipulate these cells and their receptors in a cell type‐specific and non‐invasive manner. To circumvent this limitation, we developed a transgenic mouse line (GFAP‐hM3Dq mice) that expresses an engineered Gq protein‐coupled receptor (Gq‐GPCR) known as hM3Dq DREADD (designer receptor exclusively activated by designer drug) selectively in GFAP+ glial cells. The hM3Dq receptor is activated solely by a pharmacologically inert, but bioavailable, ligand (clozapine‐N‐oxide; CNO), while bein...