SRF is required for maintenance of astrocytes in non-reactive state in the mammalian brain

ABSTRACT

Astrocytes play several critical roles in the normal functioning of the mammalian brain including ion homeostasis, synapse formation and synaptic plasticity. Following injury and infection or in the setting of neurodegeneration, astrocytes become hypertrophic and reactive, a process termed astrogliosis. Although acute reactive gliosis is beneficial in limiting further tissue damage, chronic gliosis becomes detrimental for neuronal recovery and regeneration. Several extracellular factors have been identified that generate reactive astrocytes; however, very little is known about the cell-autonomous transcriptional mechanisms that regulate the maintenance of astrocytes in the normal non-reactive state. Herein, we show that conditional deletion of the stimulus-dependent transcription factor, serum response factor (SRF) in astrocytes (Srf^GFAP-CKO) results in astrogliosis marked by hypertrophic morphology and increased expression of GFAP, vimentin and nestin. These reactive astrocytes were not restricted to any specific brain region and were seen in both white and grey matter in the entire brain. This astrogliosis persisted throughout adulthood concomitant with microglial activation. Importantly, the Srf mutant mouse brain did not exhibit any cell death or blood brain barrier (BBB) deficits suggesting that apoptosis and leaky BBB are not the causes for the reactive phenotype. The mutant astrocytes expressed more A2 reactive astrocyte marker genes and the Srf^GFAPCKO mice exhibited normal neuronal numbers indicating that SRF-deficient gliosis astrocytes are not neurotoxic. Together our findings suggest that SRF plays a critical role in astrocytes to maintain them in a non-reactive state.

SIGNIFICANCE STATEMENT In response to CNS injury, infection and in neurodegeneration, astrocytes undergo complex structural and physiological changes termed as reactive gliosis. Currently, the molecular mechanisms that regulate the non-reactive state of the astrocytes are poorly understood. We report that the SRF transcription factor is required for the maintenance of astrocytes in the non-reactive state such that its conditional deletion in astrocytes results in widespread reactive astrogliosis. The SRF-deficient reactive astrocytes are persistent, non-proliferating and are not caused by cell death or impaired blood brain barrier integrity. In this regard, SRF regulates reactive astrocyte generation in the mammalian brain in a cell-autonomous manner.