Transcriptional and functional consequences of neuron-astrocyte interactions

Astrocytes play a large number of roles essential for CNS health and are important mediators in CNS disease, demonstrating both neuroprotective and neurotoxic phenotypes. Non-cell autonomous interactions between neurons and astrocytes have been implicated in regulating astrocyte function and phenotype, but the scope and mechanisms of how neuronal signals control astrocytes are poorly understood. The data presented in this thesis describe how neuron-astrocyte interactions influence astrocyte transcriptional pathways to control homeostatic and neuroprotective functions in health and disease. First, I show that healthy astrocytes are modulated by a physiological signal: neuronal synaptic activity. Using an in vitro astrocyte-neuron co-culture model, I describe how synaptic activity alters astrocyte transcription via CREB-dependent signalling to boost the astrocyte-neuron lactate shuttle pathway – an important pathway for energy provision in the CNS. Second, by exposing astrocyte-specific EGFP-ribosome reporter mice to a light-stimulus paradigm, I demonstrate that altered synaptic activity influences astrocyte transcription in a more complex in vivo model. I further describe how activity-dependent neuronal and astrocyte transcriptional pathways are altered upwards or downwards when neuronal activity is suppressed during anaesthesia or when neuronal activity is enhanced with transcranial electrical stimulation. Finally, I explore the consequences of neurodegenerative disease on astrocyte transcription and phenotype. Using a transgenic mouse model of frontotemporal dementia (FTD), I describe how neuronal tauopathy drives upregulation of both neurotoxic and neuroprotective astrocyte transcriptional signatures. One key signature found was upregulation of the cyto-protective transcription factor Nrf2 pathway, and I demonstrate that boosting Nrf2 in reactive astrocytes confers neuroprotection in our model of human tauopathy. Collectively, these investigations add to our growing understanding of how astrocyte transcription and function are altered both by physiological signals and during neurodegeneration, and highlight the astrocyte Nrf2 pathway as a putative target for therapeutic benefit in neurodegenerative disease.