Role of astrocyte Ca2+ signaling for hippocampal spatial memory in a mouse model of familial Alzheimer’s Disease

The apparently simple routine of cycling to work along a known itinerary depends on the brain circuits of the hippocampus, which, much like a ‘gps’ system, enables spatial memory and navigation. The activity of specific hippocampal neurons, called ‘place cells’, constantly track the position of the self in space, but is also thought to store the memory of salient places and objects, which can be recalled as reference points along the correct path towards the office. These spatial memory skills are highly compromised in Alzheimer’s disease, including the rare familial form (FAD), where hippocampal circuits degenerate. The functional integrity of the hippocampus is thought to depend also on astrocytes, glial cells whose activity, regulated by intracellular Ca2+ fluctuations, nurtures and modulates neuronal activity and synaptic plasticity. However, little is known about how astrocytes participate in spatial memory and whether they are impaired in FAD. Thus, the aim of our study is to take advantage of cutting-edge technologies to record the activity of hippocampal astrocytes while mice learn to navigate novel environments. Then, using a mouse model of FAD (PS2APP), we will reveal how astrocytes impairment can affect animals’ ability to form new spatial memories. Finally, we will develop a new gene-editing technology (CRISPR-Cas9) to fix defective astrocytes signalling cascades, and determine whether restoring the correct astrocytes Ca2+ activity is sufficient to improve memory performance. By revealing new astrocytic Ca2+ signalling mechanisms underlying spatial memory, we hope our research could lead to novel potential therapeutic strategies to treat FAD.