Reactive features and neurogenic potential of striatal astrocytes upon excitotoxic lesion: role of the transcription factor SOX2 ​

Astrocytes show a heterogeneous repertoire of responses to diverse brain insults including the transition toward a neurogenic state leading to the production of a huge number of neuroblasts. However, such transition takes place only in striatal astrocytes after quinolinic acid (QA)-mediated excitotoxic lesion or stroke. The neurogenic transition of striatal astrocytes appears a complex multi-stage process as testified by the long time (3 weeks) it takes for astrocytes to start neuron production after QA-mediated lesion. However, the stage-specific events occurring in astrocytes are not fully determined. To clarify these events, we examined striatal astrocyte reactivity to QA-induced excitotoxic lesion and showed that it occurs through a time-dependent change in the cell reactive features. While GFAP expression was already present immediately after the damage and retained over time, SOX2 overexpression increased progressively until the neurogenesis onset. Astrocyte proliferation instead peaked at 7 days post-lesion (dpl) with a strong correlation with both the size of the striatal lesion and SOX2 expression levels. Moreover, we showed that astrocyte-specific SOX2 deletion abrogated astrocyte proliferation at this time point, indicating that astrocyte proliferation at 7dpl critically depends on the expression of this transcription factor. In addition, we found that SOX2 modulates the type of astrocyte reactive changes that in turn influence leukocyte infiltration and tissue remodelling. Altogether these results start to delineate the SOX2 influence on early astrocyte response to QA-induced lesion. A further step will be to determine whether and which of these changes are essential for the onset of neurogenesis.