Pre-plaque Aß-Mediated Impairment of Synaptic Depotentiation in a Transgenic Rat Model of Alzheimer’s Disease Amyloidosis

Abstract

How endogenously produced soluble amyloid ß-protein (Aß) affects synaptic plasticity in vulnerable circuits should provide insight into early Alzheimer’s disease pathophysiology. McGill-R-Thy1-APP transgenic rats, modeling Alzheimer’s disease amyloidosis, exhibit an age-dependent soluble Aß-mediated impairment of the induction of long-term potentiation (LTP) by 200 Hz conditioning stimulation at apical CA3-to-CA1 synapses. Here, we investigated if synaptic weakening at these synapses in the form of activity-dependent persistent reversal (depotentiation) of LTP is also altered in pre-plaque rats in vivo . In freely behaving transgenic rats strong, 400 Hz, conditioning stimulation induced stable LTP that was NMDA receptor- and voltage-gated Ca 2+ channel-dependent. Surprisingly, the ability of novelty exploration to induce depotentiation of 400 Hz-induced LTP was impaired in an Aß-dependent manner in the freely behaving transgenic rats. Moreover, at apical synapses, low frequency conditioning stimulation (1 Hz) did not trigger depotentiation in anaesthetized transgenic rats, with an age-dependence similar to the LTP deficit. In contrast, at basal synapses neither LTP, induced by 100 or 200 Hz, nor novelty exploration-induced depotentiation was impaired in the freely behaving transgenic rats. These findings indicate that activity-dependent weakening, as well as strengthening, is impaired in a synapse- and age-dependent manner in this model of early Alzheimer’s disease amyloidosis.

Gamma-patterned sensory stimulation reverses synaptic plasticity deficits in rat models of early Alzheimer's disease

“…To investigate any potential beneficial effects of light and sound stimulation synchronized at 40 Hz we studied pre-plaque transgenic animals first (Figure 1A,B). Consistent with our previous reports (Qi et al, 2014;Qi et al, 2019), whereas 200 Hz HFS induced robust synaptic LTP in the hippocampus of wild-type rats (Untreated WT, p=0.0059, compared with pre-HFS baseline), LTP was only transient in age-matched pre-plaque APP transgenic rats, being completely blocked at 3 h post-HFS (Untreated TG, p=0.1775, compared with pre-HFS baseline and p=0.0167, compared with Untreated WT). A two-week treatment consisting of two-hour daily sessions completely abrogated the LTP deficit in transgenic rats (40 Hz TG, p=0.0071, compared with pre-HFS baseline and p>0.9999, compared with Untreated WT, p=0.0009, compared with Untreated TG, Figure 1B).…”

Enduring glucocorticoid-evoked exacerbation of synaptic plasticity disruption in male rats modelling early Alzheimer’s disease amyloidosis

“…This finding is consistent with previous studies on the acute action of CORT on LTP induced using generally milder conditioning protocols [ 13 , 43 ]. The latter protocols induce NMDA receptor-dependent LTP whereas sHFS-induced LTP is also voltage-gated Ca 2+ channel-dependent [ 26 , 28 ]. Here, short-term CORT acutely impaired a relatively late (3 h) phase of LTP while an earlier phase of LTP (<1 h) appeared unscathed.…”

“…Cognitive function is impaired before the formation of plaques, as early as 3 months of age [ 25 ]. We chose to inject animals at an age (4–5 month) when LTP is impaired by the build-up of Aß oligomers but prior to the deposition of plaques [ 26 , 27 ]. All experiments were carried out in accordance with the approval of the Health Products Regulatory Authority, Ireland, using methods similar to those described previously [ 22 ].…”

“…To induce LTP we used a strong high frequency stimulation (sHFS) protocol consisting of 3 sets of 10 trains of 20 stimuli at high intensity (75% maximum) at 400 Hz with an inter-train interval of 2 s and an inter-set interval of 5 min [ 22 ]. The form of LTP induced by sHFS is both NMDA receptor-dependent and voltage-gated Ca2+ channel-dependent [ 26 , 28 ]. For non-recovery experiments, only used in the Mcc950 study, the implantation procedure was comparable [ 22 ] but the rats were anaesthetised with urethane (1.5 g/kg, i.p.).…”

Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models

“…Previously, Kim et al [31] demonstrated that the Aß-containing C-terminus of ß-APP (CT; the product of β-secretase cleavage of APP) reversed LTP when applied 10 min after LTP induction, while Huh et al [26] showed that DP could not be induced in slices from aged Tg2576, a transgenic mouse model harboring the APP 695 SWE mutation. A very recent in vivo study by Qi et al [57] reported that 4–6-month-old, anaesthetized, pre-plaque TG (McGill-R-Thy1-APP) rats developed only a transient DP at apical synapsed in the CA1 region upon LFS at 1 Hz, while the same stimulation caused complete LTP reversal in WT animals. Interestingly, DP could be rescued by application of an antibody that specifically binds Aß oligomers.…”