Reactive astrocytes

We study astrocytes, a type of brain glial cells that play key supporting roles for neurons. Under pathological conditions, such as neurodegenerative diseases, astrocytes become reactive. This is defined by morphological changes, but the functional consequences remain unclear (Ben Haim et al., Front. Cell. Neuro., 2015; Escartin et al., Glia, 2019). Given the importance of astrocytes for brain homeostasis, any change in their functions may have major effects on neurons. 

We develop molecular tools to modulate and monitor reactive astrocytes in situ, in order to better understand the roles of these complex cells.

1. Viral vectors to selectively modulate astrocyte reactivity in vivo
We identified the JAK2-STAT3 pathway as a key signaling pathway controlling the reactive state of astrocytes in neurodegenerative diseases (Ben Haim et al., J. Neurosci., 2015; Ceyzériat et al., Neuroscience, 2016; Ceyzériat et al., Acta Neuropathol. Com., 2018). We have developed viral vectors to target this pathway in astrocytes in vivo and to manipulate their reactive state. With these molecular tools, it is possible to:

 

2. Molecular and functional changes in reactive astrocytes in vivo
Our earlier in vivo studies of reactive astrocytes induced by the cytokine CNTF, revealed significant changes in multiple astrocyte functions (Escartin et al. J. Neurosci, 2006; 2007; Seidel et al., Glia, 2015). Thanks to a FRC grant, we further showed that reactive astrocytes alter synaptic transmission and plasticity in the hippocampus (Ceyzériat et al., Acta Neuropathol. Com., 2018). Through grants from ANR and Fondation Maladies Rares, we are now exploring the molecular and functional heterogeneity of reactive astrocytes, and implement multi-omics analysis of reactive glial cells in brain diseases. 

 3. Reactive astrocytes as biomarkers for pathological situations 
Reactive astrocytes appear under pathological conditions, and thus could be used as biomarkers for brain diseases. In collaboration with brain imaging teams in MIRCen, we showed that reactive astrocytes are detected by positron emission tomography (PET) with radiotracers for TSPO, a protein previously described as a reactive microglia marker (Lavisse et al. J. Neurosci., 2012).

4. Reactive astrocytes as therapeutic targets for neurodegenerative diseases
Finally, through grants from ANR, LECMA/Vaincre Alzheimer, FRC and Neuratris, we assess whether reactive astrocytes impact molecular, cellular, functional and behavioral disease outcomes, in mouse models of Huntington's and Alzheimer's diseases (HD and AD), and more recently of demyelinating disorders. We find that reactive astrocytes have beneficial effects in HD (Escartin et al., J. Neurosci., 2006; Ben Haim et al., J. Neurosci., 2015) while they have mainly deleterious impacts in AD models (Ceyzériat et al., Acta Neuropathol. Com., 2018 ; Guillemaud et al., Neurobiol Aging, 2020).

​Virus-mediated expression of SOCS3 in astrocytes in an AD mouse model (3xTg) blunts astrocyte reaction and restores synaptic long term potentiation, a form of synaptic plasticity. 
Ceyzériat et al., Acta Neuropathol. Com., 2018. In collaboration with A. Panatier.

Grants and Awards