Impact of blunting astrocyte activity on hippocampal synaptic plasticity in a mouse model of early Alzheimer's disease based on amyloid‐β peptide exposure

Amyloid‐β peptides (Aβ) accumulate in the brain since early Alzheimer's disease (AD) and dysregulate hippocampal synaptic plasticity, the neurophysiological basis of memory. Although the relationship between long‐term potentiation (LTP) and memory processes is well established, there is also evidence that long‐term depression (LTD) may be crucial for learning and memory. Alterations in synaptic plasticity, namely in LTP, can be due to communication failures between astrocytes and neurons; however, little is known about astrocytes' ability to control hippocampal LTD, particularly in AD‐like conditions. We now aimed to test the involvement of astrocytes in changes of hippocampal LTP and LTD triggered by Aβ1–42, taking advantage of L‐α‐aminoadipate (L‐AA), a gliotoxin that blunts astrocytic function. The effects of Aβ1–42 exposure were tested in two different experimental paradigms: ex vivo (hippocampal slices superfusion) and in vivo (intracerebroventricular injection), which were previously validated to impair memory and hippocampal synaptic plasticity, two features of early AD. Blunting astrocytic function with L‐AA reduced LTP and LTD amplitude in hippocampal slices from control mice, but the effect on LTD was less evident, suggesting that astrocytes have a greater influence on LTP than on LTD under non‐pathological conditions. However, under AD conditions, blunting astrocytes did not consistently alter the reduction of LTP magnitude, but reverted the LTD‐to‐LTP shift caused by both ex vivo and in vivo Aβ1–42 exposure. This shows that astrocytes were responsible for the hippocampal LTD‐to‐LTP shift observed in early AD conditions, reinforcing the interest of strategies targeting astrocytes to restore memory and synaptic plasticity deficits present in early AD. To study the impact of astrocytes on hippocampal synaptic plasticity changes under early Alzheimer's disease (AD), we used two different experimental paradigms of Aβ1–42 exposure: ex vivo superfusion of hippocampal slices and in vivo through intracerebroventricular injection of this peptide, and the gliotoxin L‐α‐aminoadipate (L‐AA) that blunts astrocytic function. Data showed that under AD conditions, there is a decrease of hippocampal long‐term potentiation (LTP) and the long‐term depression (LTD) shifted toward LTP. The blunting of astrocytes activity was able to restore the LTD impairment caused by both ex vivo and in vivo Aβ1–42 exposure.