Amyloid Beta42 oligomers up‐regulate the excitatory synapses by potentiating presynaptic release while impairing postsynaptic NMDA receptors

Abstract

Key points NMDA receptors (NMDARs) are key molecules for controlling neuronal plasticity, learning and memory processes. Their function is impaired during Alzheimer's disease (AD) but the exact consequence on synaptic function is not yet fully identified. An important hallmark of AD onset is represented by the neuronal accumulation of Amyloid Beta42 oligomers (Abeta42) that we have recently shown to be responsible for the increased intracellular Ca2+ concentration through Ryanodine Receptors (RyRs) Here we characterized the effects of Abeta42 oligomers on NMDA synapses showing specific pre‐ and post‐synaptic functional changes that lead to a potentiation of basal and synchronous NMDA synaptic transmission. These overall effects can be abolished by decreasing Ca2+ release from RyRs with specific inhibitors that we propose as new pharmacological tools for AD treatment. Abstract We have recently shown that Abeta42 oligomers (Abeta42) cause calcium dysregulation in hippocampal neurons by stimulating Ca²⁺ release from ryanodine receptors (RyRs) and inhibiting Ca²⁺ entry through NMDA receptors (NMDARs). Here, we found that Abeta42 decreases the average NMDA‐activated inward current and that Ca²⁺‐entry through NMDARs is accompanied by Ca²⁺ release from the stores. The overall amount of [Ca²⁺]_i increase during NMDA application is 50% associated to RyRs opening and 50% to NMDARs activation. Addition of Abeta42 does not change this proportion. We estimated the number of NMDARs expressed in hippocampal neurons and their unitary current. We found that Abeta42 decreases the number of NMDARs without altering their unitary current. Paradoxically, the oligomer increases the size of electrically evoked eEPSCs induced by NMDARs activation. We found that this is the consequence of the increased release probability (p) of glutamate and number of release sites (N) of NMDA synapses, while the quantal size (q) is significantly decreased as expected from the decreased number of NMDARs. An increased number of release sites induced by Abeta42 is also supported by the increased size of the ready releasable pool (RRPsyn) and by the enhanced percentage of paired pulse depression (PPD). Interestingly, the RyRs inhibitor dantrolene prevents the increase of PPD induced by Abeta42 oligomers. In conclusion, Abeta42 up‐regulates NMDA synaptic responses with a mechanism involving RyRs that occurs during the early stages of AD onset. This suggests that new selective modulators of RyRs may be useful for designing effective therapies to treat AD patients. This article is protected by copyright. All rights reserved