Reactive gliosis at the tripartite synapse Functional characterization of astrocytes in a model of Alzheimer’s disease

Astrocytes are the most numerous macroglia in the central nervous system and are crucial in basic homeostatic functions in the brain, including regulating the extracellular ionic and water balance, maintaining the blood-brain-barrier, regulating synaptic numbers and strength, playing an important role in immune signaling, and controlling cerebral blood flow and energy metabolites for neurons. Due to their close relationship with neurons and other macro- and microglia, astrocytes are intimately connected with brain pathology and may be critical in brain repair or conversely may contribute to further damage in the disease process. Under pathological conditions astrocytes undergo a process referred to as reactive gliosis. In Alzheimer’s disease glia react to amyloid, and this is a model of chronic reactive gliosis. The research focused in this thesis addresses several fundamental questions concerning astrocyte physiology and how reactive gliosis affects their functional state. Firstly, transcriptomic changes in astrocytes were studied to determine global cortical changes occurring in a mouse model of Alzheimer’s disease (APP/PS1) – chapter 2. A question that arose from this research was subsequently addressed in chapter 3, namely whether the functionality of potassium channel Kir4.1 is compromised in APP/PS1 mice due to reactive gliosis and amyloid deposition. Lastly, from previous research it has become clear that astrocytes in the APP/PS1 model show alterations in Ca²⁺-signaling. We were interested in whether these same changes in Ca²⁺ dynamics could be found in the dentate gyrus and what the consequence of these alterations might be for neuronal function (chapter 4).