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

Yingjie Qi,Michael J Rowan,Igor Klyubin,Tomas Ondrejcak,Neng-Wei Hu

doi:10.3389/fnins.2019.00861

Yingjie Qi, Michael J Rowan + Show 3 more

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https://doi.org/10.3389/fnins.2019.00861

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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 Ca2+ 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.

Highlights

There is great interest in understanding how different forms of synaptic plasticity contribute to normal brain function and how disruption of these physiological processes may underlie key aspects of the pathophysiology of neurodegenerative diseases
The long-term potentiation (LTP) deficit in pre-plaque transgenic rats appears to be mediated by an agedependent pro-inflammatory milieu in the hippocampus (Leon et al, 2010; Hanzel et al, 2014; Iulita et al, 2014; Qi et al, 2018) driven by amyloid ß (Aß) oligomer binding to cellular prion protein and glutamate acting at metabotropic glutamate receptor 5 (Zhang D. et al, 2017)
Endogenous Aß-mediated inhibition of both LTP and depotentiation was restricted to apical synapses, with neither LTP nor depotentiation in TG rats being significantly altered at basal synapses. These findings indicate that in addition to synapse-selective deficits in LTP induction, the synaptic plasticity mechanisms for timedependent weakening of previously strengthened synapses are disrupted by Aßo in early pre-plaque Alzheimer’s disease (AD) amyloidosis

Summary

Introduction

There is great interest in understanding how different forms of synaptic plasticity contribute to normal brain function and how disruption of these physiological processes may underlie key aspects of the pathophysiology of neurodegenerative diseases. LTP decay/reversal is an active process and mechanisms underlying depotentiation are believed to play important roles in the time- and state- dependent erasure of certain forms of memory. The LTP deficit in pre-plaque transgenic rats appears to be mediated by an agedependent pro-inflammatory milieu in the hippocampus (Leon et al, 2010; Hanzel et al, 2014; Iulita et al, 2014; Qi et al, 2018) driven by Aß oligomer binding to cellular prion protein and glutamate acting at metabotropic glutamate receptor 5 (Zhang D. et al, 2017). An early intracellular buildup of Aß oligomers correlates with impairment of hippocampusdependent memory (Leon et al, 2010; Hanzel et al, 2014; Iulita et al, 2014) in the absence of observable synaptic structural change (Martino Adami et al, 2017)

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