Rescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in an Alzheimer’s disease mouse model

Alzheimer’s disease (AD) is a chronic incurable neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunctions. Brain function is governed by dynamic interactions between neurons and glial cells. Over the last decades it has been shown that calcium dynamics in astrocytes represent a fundamental signal that through gliotransmitter release regulates synaptic plasticity and behaviour. Here, by using cutting-edge techniques including 2-photon Ca2+ imaging, electrophysiology and behavioural memory tests, we present a longitudinal study in the PS2APP mouse model of AD linking astrocyte Ca2+ hypoactivity to memory loss. At the onset of plaque deposition, somatosensory cortical astrocytes of AD female mice swtich to a reactive pro-inflammatory state and exhibit a drastic reduction of Ca2+ signaling, closely associated with decreased endoplasmic reticulum Ca2+ concentration and reduced expression of the Ca2+ sensor STIM1. In parallel, astrocyte-dependent long-term synaptic plasticity declines in the somatosensory circuitry, anticipating specific tactile memory loss. Notably, we show that both astrocyte Ca2+ signaling and long-term synaptic plasticity are fully recovered by selective STIM1 overexpression in astrocytes. Our data unveil astrocyte Ca2+ hypoactivity in neocortical astrocytes as a functional hallmark of early AD stages and indicate astrocytic STIM1 as a target to rescue memory deficits.