Group leader: Carole Escartin

Astrocyte signaling in health and neurodegenerative diseases

In brief

Astrocytes have crucial circuit-specific interactions with neurons, regulating synaptic activity and plasticity at multiple timescales. Their potential role in modulating complex behaviors is emerging, but still under-investigated, especially in disease, where astrocytes display major but still unclear changes. Studies on astrocyte regulation of synaptic activity focus mainly on calcium signaling. However, we and others showed that other signaling cascades play central roles in astrocytes, including transcription factor-based cascades such as the JAK-STAT3 pathway, which controls key molecular and functional features in astrocytes, with long-lasting impacts on neurons in disease models.
We aim to understand how these alternative signaling modalities in astrocytes shape neuronal function, from synapse to behavior in health and disease.

signaling central pathway

1. Refined tools to monitor and modulate astrocytes in vivo

We identified the JAK2-STAT3 pathway as a key signaling pathway controlling the reactive state of astrocytes in neurodegenerative diseases. We have developed viral vectors to target this pathway and manipulate astrocytes in vivo. In combination with new viral vector-based reporters and chemogenetic constructs, we now aim to:
• Understand what reactive astrocytes do in specific disease contexts, using fluorescent-activated cell sorting, transcriptomics, proteomics, functional and histological analysis as well as behavioral assessment (part 2).
• Implement new therapeutic strategies for brain diseases by targeting specific populations of reactive astrocytes (part 3).
• Integrate longitudinal brain and cellular imaging techniques to monitor astrocytes and their signaling cascades in situ, using 2-photon microscopy and fiber photometry; but also their effects on brain-wide network activity using fMRI.
• Develop novel tools to monitor and manipulate transcription factor-based pathways in vivo, including non-canonical STAT3 signaling and immediate early gene signaling, which remain underexplored in astrocytes.

2. Molecular and functional changes regulated by transcription factor-based signaling in astrocytes in vivo

We have reported circuit-specific effects of the JAK2-STAT3 pathway in astrocytes, which regulates synaptic plasticity and learning in the dorsal mouse hippocampus and socio-sexual behavior in the ventral mouse hippocampus.
Recently, we showed that STAT3-dependent reactive astrocytes promote proteostasis in Huntington’s disease models by bi-directional neuron-astrocyte communication.
We are also implementing multi-omics analysis of astrocytes in brain diseases, contributing with a biologist-friendly app for -omic data visualization and analysis.

3. Astrocytes as therapeutic agents for neurodegenerative diseases

changements moleculaires et fonctionnels We assess how reactive astrocytes impact multiple outcomes in mouse models of brain diseases. We showed that STAT3-dependent reactive astrocytes have beneficial roles in models of Huntington’s disease, while they have mainly deleterious effects in Alzheimer’s disease models. We are now assessing the therapeutic efficacy of targeting specific sub-populations of reactive astrocytes, depending on their signaling. We are also investigating whether astrocytes contribute to some neuropsychiatric symptoms observed in neurodegenerative diseases.
2024-2027. Équipe FRM grant
2020-2021. Retour en France fellowship to L. Ben Haim		 Fondation recherche medicale
Alzheimer France 2022-2026. Grant coordinated by E. Nivet (INP, Marseille)
2020-2024. Grant coordinated by S. Betuing (Sorbonne Université, Paris)
2017-2018. Tremplin-ERC grant to C. Escartin
2011-2015. Grant coordinated by N. Rouach (Collège de France)
2010-2014. Young Investigator (JCJC) grant to C. Escartin
Alzheimer France
 2023-2025. Grant coordinated by H. Hirbec (IGF, Montpellier)
2019. Prix Joël Ménard to C. Escartin.
2022-2025. Grant to C. Escartin, with N. Rouach (Collège de France)
2021-2023. Grant coordinated by M. Cohen-Salmon (Collège de France)		 Alzheimer France
22020. MSCA reintegration fellowship to L. Ben Haim (declined) Action Marie Curie
2021-2023. Grant to C. Escartin and S. Bétuing (Sorbonne Université)
2018-2021. Grant to C. Escartin and F. Ortiz (Univ. Autónoma de Chile)		 Neuractris
Fondation vaincre Alzheimernce 2021-2022. Pilot Award to L. Ben Haim
2016-2018. Project grant to C. Escartin

2019-2020. GenOmics. Grant2018-2019. Research grant
to C. Escartin, with E. Bonnet (CNRGH, Evryy) to C. Escartin

fondation maladies rares Association Huntington France

2017. CNRS Bronze medal 2016-2018. Grant to C. Escartin,
awarded to C. Escartin with A. Panatier (Neurocentre Magendie, Bordeaux)

medaille-bronze-cnrs Federation recherche cerveau
Selected publications
* equal contribution

2023

• Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway. Abjean L, Ben Haim L*, Riquelme-Perez M*, Gipchtein P, Derbois C, Palomares MA, Petit F, Hérard AS, Gaillard MC, Guillermier M, Gaudin-Guérif M, Aurégan G, Sagar N, Héry C, Dufour N, Robil N, Kabani M, Melki R, De la Grange P, Bemelmans AP, Bonvento G, Deleuze JF, Hantraye P, Flament J, Bonnet E, Brohard S, Olaso R, Brouillet E, Carrillo-de Sauvage MA, Escartin C. Brain. 2023. 146(1): 149–66 DOI: 10.1093/brain/awac068

2022

• DEVEA: an interactive shiny application for Differential Expression analysis, data Visualization and Enrichment Analysis of transcriptomics data. Riquelme-Perez M*, Perez-Sanz F*, Deleuze JF, Escartin C, Bonnet E, Brohard S. F1000Res. 2022. 28;11:711 DOI: 10.12688/f1000research.122949.2

2021

• Astrocytes and neuropsychiatric symptoms in neurodegenerative diseases: Exploring the missing links. Ben Haim L, Escartin C. Curr Opin Neurobiol. 2021. 72:63-71 DOI: 10.1016/j.conb.2021.09.002

• Reactive astrocyte nomenclature, definitions, and future directions. Escartin C*, Galea E*, […77 authors…], Sofroniew MV*, Verkhratsky A.* Nat Neurosci. 2021. 24 : 312-25 DOI: 10.1038/s41593-020-00783-4

2020

• Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease. Guillemaud O*, Ceyzériat K*, Saint-Georges T, Cambon K, Petit F, Ben Haim L, Carrillo-de Sauvage MA, Guillermier M, Bernier S, Hérard AS, Joséphine C, Bémelmans AP, Brouillet E, Hantraye P, Bonvento G, Escartin C. Neurobiology of Aging. 2020. 90:135-46 DOI: 10.1016/j.neurobiolaging.2020.02.010

2019

• Questions and (some) answers on reactive astrocytes. Escartin C, Guillemaud O, Carrillo-de Sauvage M. Glia. 2019. 67(12):2221-47 DOI: 10.1002/glia.23687

2018

• Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease.
Ceyzériat K, Ben Haim L, Denizot A, Pommier D, Matos M, Guillemaud O, Palomares MA, Abjean L, Petit F, Gipchtein P, Gaillard MC, Guillermier M, Bernier S, Gaudin M, Aurégan G, Joséphine C, Dechamps N, Veran J, Langlais V, Cambon K, Bémelmans A, Baijer J, Bonvento G, Dhenain M, Deleuze JF, Oliet SHR, Brouillet E, Hantraye P, Carrillo de Sauvage MA, Olaso R, Panatier A, Escartin C. Acta Neuropathologica Communications. 2018. 6(1):104 DOI: 10.1186/s40478-018-0606-1

• Kir4.1-Dependent astrocyte-fast motor neuron interactions are required for peak strength. Kelley KW*, Ben Haim L*, Schirmer L, Tyzack GE, Tolman M, Miller JG, Tsai HH, Chang SM, Molofsky AV, Yang Y, Patani R, Lakatos A, Ullian EM, Rowitch DH. Neuron. 2018.98(2):306-19 DOI: 10.1016/j.neuron.2018.03.010

2017

• Functional diversity of astrocytes in neural circuit regulation. Ben Haim L, Rowitch DH. Nat Rev Neurosci. 2017. 18(1):31-41 DOI: 10.1038/nrn.2016.159

2015

• The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s disease. Ben Haim L, Ceyzériat K, Carrillo-de Sauvage M-A, Aubry F, Auregan G, Guillermier M, Ruiz M, Petit F, Houitte D, Faivre E, Vandesquille M, Aron-Badin R, Dhenain M, Déglon N, Hantraye P, Brouillet E, Bonvento G, Escartin C. J Neurosci. 2015. 35(6):2817-29 DOI: 10.1523/JNEUROSCI.3516-14.2015

2012

• Reactive astrocytes overexpress TSPO and are detected by TSPO PET imaging. Lavisse S, Guillermier M, Hérard AS, Petit F, Delahaye M, Van Camp N, Ben Haim L, Lebon V, Remy P, Dollé F, Delzescaux T, Bonvento G, Hantraye P, Escartin C. J. Neurosci. 2012. 32(32):10809-18 DOI: 10.1523/JNEUROSCI.1487-12.2012

PhD students

• Miriam Riquelme-Perez Doctorante. 2019-2023
• Juliette Lopez-Hanotte. Doctorante en échange. Univ. de la Plata, Argentina. 2022-23
• Océane Guillemaud. Master 2 + Doctorante. 2017-20
• Laurene Abjean. Master 2 + Doctorante. 2015-19
• Elena Saavedra-Lopez. Doctorante en échange.Univ. Autonoma de Barcelona. 2018
• Kelly Ceyzériat. Master 2 + Doctorante. 2014-17
• Lucile Ben Haim. Master 2 + Doctorante. 2011-14

Master students

• Anirudh Krishna. Master. Mohali Institute of Research, Inde. 2022-23
• Mie Moller-Clausen. Licence 3. Univ. of Copenhagen, Danemark. 2022-23
• Andrea Dubet. Master 1, Aix-Marseille Univ. 2022
• Cameron Héry. Master 2, Sorbonne Univ. 2021-22
• Raul Pulgar Sepulveda. Stagiaire. Univ. Autonoma de Chile, Chili. 2019
• Thomas Saint-Georges. Master 2. 2016
• Marion Delahaye. Master 2. 2010
• Ana-Clara Bobadilla. Master 1. 2009

Post-docs

• Lucile Ben Haim. Post-doctorante “Retour en France”, FRM. 2020-21
• Ludmila Juricek. ANR. 2017-19
• Maria-Angeles Carrillo-de Sauvage. ANR. 2011-13

Engineers & Technicians

• Vivien Letenneur. Ingénieur. 2022-24
• Fabien Aubry. Technicien ANR. 2012-13