Partial Suppression of Ca _v2.1 Function Prevents Synaptic and Behavioral Impairments in Alzheimer's Disease Models

Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau

“…If this enhanced LTD is indeed due to enhanced release probability, then normalizing presynaptic function should rescue the effect. We have previously shown that a low (50 nM) dose of the presynaptic Ca V 2.1 voltage-gated Ca 2+ channel blocker u-agatoxin IVA (AgTx) restores normal release probability in the presence of Ab o under these same experimental conditions (Jeans et al, 2020), and we confirmed that this treatment alone had no effect on LTD compared with control (80.26% ± 8.99% of baseline; n = 5). However, lowdose AgTx fully rescued the effect of Ab o on LTD (76.08% ± 4.64% of baseline; n = 6) (Figures 1G and 1H), suggesting that enhanced presynaptic function is required for the Ab o -mediated enhancement of LTD. To strengthen this conclusion, we repeated the experiment using a different manipulation, treatment with 20 mM adenosine, to normalize release probability (Figures S1A and S1B).…”

“…Initially, we sought to confirm that glutamate release probability is elevated at CA3-CA1 (Schaffer collateral) synapses in this experimental model. Because α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization, which rapidly follows exposure to Aβ o ( Li et al., 2009 ), limits the ability of electrophysiological measurements to detect changes in release probability ( Jeans et al., 2020 ), we used an optical method to measure release from the presynaptic bouton directly. FM1-43 is an activity-dependent dye label that allows for direct imaging of synaptic vesicle fusion ( Kavalali and Jorgensen, 2014 ).…”

“… (B) Western blot analysis of hippocampal slices treated for 7 days as indicated. Low-dose (50 nM) ω-agatoxin IVA (AgTx) treatment restores elevated release probability to normal levels ( Jeans et al., 2020 ). Left panels show representative bands.…”

“…We then asked whether normalization of glutamate release probability with low-dose AgTx ( Jeans et al., 2020 ), which rescues the enhancement of LTD by Aβ o ( Figures 1 G and 1H), was also able to prevent the hyperphosphorylation of tau. Slices were incubated in AgTx alone, or AgTx with Aβ o , and tau phosphorylation was examined as before.…”

“…Both LTP impairment and facilitation of LTD appear to require the activation of extrasynaptic N-methyl-D-aspartate subtype glutamate receptors (NMDARs), which can result from Ab o -mediated impairments in the uptake and clearance of synaptically released glutamate (Li et al, 2009(Li et al, , 2011. However, several studies have indicated that Ab o can also enhance action potential-evoked synaptic glutamate release (Brito-Moreira et al, 2011;Dolev et al, 2013;Jeans et al, 2020;Kabogo et al, 2010;Russell et al, 2012), although this remains controversial (He et al, 2019;Nimmrich et al, 2008), and we hypothesized that such enhanced release could represent another source of excess glutamate that might potentially contribute to extrasynaptic NMDAR activation and plasticity changes. Under physiological conditions, certain forms of plasticity are associated with the phosphorylation of tau; specifically, glycogen synthase kinase 3b (GSK-3b)-mediated phosphorylation of tau at serine 396 is critical for both induction of hippocampal LTD and the reversal of learning in vivo (Kimura et al, 2013;Regan et al, 2015).…”