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

Abstract

Amyloidβ 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 ADlike conditions. We now aimed to test the involvement of astrocytes in changes of hippocampal LTP and LTD triggered by Aβ 1-42 , taking advantage of Lα-aminoadipate (L-AA), a gliotoxin that blunts astrocytic function. The effects of Aβ 1-42 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 Aβ 1-42 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.

Adenosine A2A Receptor Up-Regulation Pre-Dates Deficits of Synaptic Plasticity and of Memory in Mice Exposed to Aβ1–42 to Model Early Alzheimer’s Disease

“…The normalizing effect of SCH58261 in slices collected 15-16 days after Aβ-icv was similar to that previously described [41,53]. Thus, SCH58261 (50 nM) reverted (p < 0.001, Student's t test) the Aβ-induced decrease in LTP magnitude (27.2.4 ± 3.2% over baseline, n = 8, in the absence and 57.9 ± 3.6% over baseline, n = 8, in the presence of SCH58261) ((Figure 3F,G); note that the vehicle-icv and Aβ-icv groups in Figure 3F,G are the same as in Figure 2D,E).…”

Astrocytic A2A receptors silencing negatively impacts hippocampal synaptic plasticity and memory of adult mice

“…In fact, hippocampal LTP is impaired by the selective manipulation of astrocytes using either glial toxins (Han et al, 2015;Pereira et al, 2021) or different pharmacological tools (Henneberger et al, 2010;Sherwood et al, 2017;Walrave et al, 2016;Zhu et al, 2022) or different genetic (Filosa et al, 2009;Hösli et al, 2022;Park et al, 2015;Robin et al, 2018;Skucas et al, 2011;Suzuki et al, 2011;Yang et al, 2013) or chemogenetic manipulations (Adamsky et al, 2018;Van Den Herrewegen et al, 2021). Although supported by fewer studies, there is also previous evidence that astrocytes also impact on LTD in the hippocampus (Han et al, 2012;Huang et al, 2018;Lopes et al, 2022;Skucas et al, 2011) and in synapses of other brain areas (Butcher et al, 2022;Navarrete et al, 2019).…”

“…Input/output curves (fEPSP slope plotted vs. stimulus intensity) were acquired to evaluate basal transmission and to select the stimulation intensity. In LTP experiments, an intensity of the stimulus that evoked a fEPSP of approximately 40% was used and LTP was evoked by high‐frequency stimulation (HFS, one train of 100 Hz for 1 s), which has previously been used to characterize the impact of synaptic A 2A R on LTP magnitude (Lopes et al, 2022; Moreira‐de‐Sá et al, 2020). In LTD experiments, a stimulus intensity triggering 60% of the maximal slope was used and LTD was induced by low frequency‐stimulation (LFS) consisting of 3 trains of 1500 pulses at 2 Hz with a intertrain interval of 10 minutes, which are the experimental conditions where we previously characterized the impact of A 2A R on LTD (Moreira‐de‐Sá et al, 2020; Temido‐Ferreira et al, 2020).…”

“…After the electrophysiological recordings, the slice was sectioned as previously described (Lopes et al, 2022) for immunohistochemical confirmation that recordings were carried out in the vicinity of transfected cells. The slice was fixed by immersion in a 4% paraformaldehyde (Sigma‐Aldrich) solution during 2 days, then transferred into a 30% sucrose solution for 2 days, before washing with saline phosphate buffer (PBS, composed of NaCl 137 mM, KCl 2.7 mM, Na 2 HPO 4 10 mM and KH 2 PO 4 1.9 mM, pH 7.4).…”

The role of ADAM10 in astrocytes: Implications for Alzheimer’s disease

“…In addition, Aβ may interact with astrocytes to reduce phagocytosis and the clearance of dystrophic synapses leading to neuron functional deficits ( Afridi et al, 2020 ; Sanchez-Mico et al, 2021 ). Thus, healthy functional astrocytes may promote non-amyloidogenic APP processing by ADAM10 and increase neuronal plasticity which could be neuroprotective in AD ( Lopes et al, 2022 ).…”