Astrocyte Ca²⁺ Dysregulation in Alzheimer's Disease Mouse Models: Revisiting the Dogma of Hyperactivity

Astrocytes are essential gatekeepers of brain homeostasis, and the disruption of their functions can contribute to the development of several neurological diseases. Among astrocyte signaling pathways, the intracellular second messenger Ca²⁺ plays a pivotal role in regulating the release of gliotransmitters, which actively modulate fundamental processes in the brain such as synaptic plasticity and memory function. Several studies over the years support the idea that dysregulated astrocytic Ca²⁺ homeostasis represents a relevant mechanism in Alzheimer's disease pathogenesis. Early works in transgenic mice modelling Alzheimer's disease reported increased Ca²⁺ activity in astroglial cells, supporting the idea of hyperactivity as a common trait of astrocytes in this pathology. However, recent studies have described astrocyte Ca²⁺ hypoactivity in various mouse models, revealing a more complex and heterogeneous scenario. In this review, we summarize and critically discuss the main studies addressing the direction(s) of astrocytic Ca²⁺ signaling dysfunction in mouse models of Alzheimer's disease. We prioritize investigations performed in ex vivo and in vivo conditions, carefully comparing the different experimental approaches used to measure Ca²⁺ activity in astrocytes. By integrating results across multiple mouse models and methodological strategies, we aim to provide a more complete picture of astrocyte Ca²⁺ dysregulation in Alzheimer's disease.