Selective modulation of activated astrocytes: In vivo monitoring by magnetic resonance and contribution to neuronal death in Huntington’s disease – ACTIVASTRO

During this project, we have developed lentiviral vectors that allow controlled activation or deactivation of astrocytes in the rodent brain. After validation of these vectors by immunohistochemistry, biochemistry and molecular biology, we are evaluating the selectivity of different imaging techniques (magnetic resonance spectroscopy and positron emission tomography, TEP) to monitor astrocyte reactivity in situ. Finally, we study the contribution of reactive astrocytes in transgenic mouse models of Huntington's disease, a chronic neurodegenerative disease. The consequences of reactive astrocyte manipulation are characterized at the behavioral, anatomical, cellular and molecular levels.

We now have viral vectors to activate or de-activate astrocytes in the rodent brain (Ben Haim et al., in revision).
Using magnetic resonance spectroscopy and imaging, we showed that the concentrations of several brain metabolites are modified by the reactive state of astrocytes (Carrillo de Sauvage et al., submitted). We also demonstrated that TEP imagin with specific radioligands for the translocator protein is able to detect reactive astrocytes in situ (Lavisse et al., J. Neuroscience, 2012). These two non-invasive imaging techniques could be used to monitor astrocyte reactivity in the brain, as an index of neuronal dysfunction.

This project has contributed to develop molecular tools to modulate astrocyte status in situ. We are using these tools to evaluate the contribution of reactive astrocytes to Huntington’s disease, but they can be used for other neurodegenerative diseases. The manipulation of astrocytes, which are supportive cells for neurons, represents an alternative and potent therapeutic strategy for many brain diseases.

These results were presented through 13 national and international talks and 10 posters at international conferences.
Part of this work was published in a research article (Lavisse et al., J. Neurosci., 2012, which illustrates the ability of PET imaging to monitor reactive astrocytes in the rodent brain) and two review articles and an editorial on astrocytes.
Two articles are under submission.

Reactive astrocytes are associated with numerous pathological situations in the brain. They are observed at early stages in patients with neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases, in vulnerable brain areas. In normal physiological conditions, astrocytes are involved in key brain functions such as regulation of brain energy metabolism, oxidative stress, blood flow and synaptic transmission. Those same functions are altered in neurodegenerative diseases sometimes before major neuronal degeneration. Reactive astrocytes may promote neuronal recovery and survival following acute injuries such as traumatic brain injury or stroke. However, their role and function in chronic diseases are still unclear and controversial, mainly due to the lack of appropriate models to assess reactive astrocyte function and imaging techniques to follow them in situ.
Manipulating the status of astrocytes –pleiotropic cells in support of neurons–represents a promising therapeutic strategy to promote neuronal survival in various pathological conditions.
We propose to develop molecular tools to evaluate the contribution of reactive astrocytes to neurodegeneration in vivo and validate brain imaging techniques to monitor astrocyte status in situ. We will develop lentiviral vectors that allow a controlled activation or deactivation of astrocytes in the rodent brain by targeting the JAK-STAT3 pathway, which is involved in astrocyte reactivity. After validation of these vectors by immunohistology, biochemistry and molecular biology, we will evaluate the selectivity of magnetic resonance imaging and spectroscopy indexes to monitor astrocyte activation in situ. Finally, we will evaluate the neuroprotective potential of manipulating astrocyte status in a transgenic mouse model of Huntington’s disease, as a prototypic chronic neurodegenerative disorder.
This translational project will provide (1) molecular tools to manipulate astrocytes in vivo, (2) validated preclinical brain imaging techniques to monitor astrocyte activation in situ and (3) an evaluation of the therapeutic potential of the selective manipulation of reactive astrocytes for chronic neurodegenerative diseases.
This multidisciplinary project will be coordinated by Carole Escartin, a young researcher who joined the CEA/CNRS URA 2210 laboratory in 2008 and will strengthen the development of a team focused on reactive astrocytes. This laboratory is based at the MIRCen Center (Molecular Imaging Research Center, www-dsv.cea.fr/MIRCen) which offers varied state-of-the-art technologies with dedicated staff within platforms, and scientific expertise, ranging from brain gene transfer, experimental therapeutics to brain imaging by nuclear magnetic resonance. This unique conjunction of techniques and expertise will favour the success of this ambitious, multidisciplinary and novel project.