Local and Use-Dependent Effects of β-Amyloid Oligomers on NMDA Receptor Function Revealed by Optical Quantal Analysis

Beta amyloid (A beta) triggers the elimination of excitatory synaptic connections in the CNS, an early manifestation of Alzheimer's disease. Oligomeric assemblies of A beta peptide associate with excitatory synapses resulting in synapse elimination through a process that requires NMDA-type glutamate receptor activation. Whether A beta affects synaptic NMDA receptor (NMDAR) function directly and acts locally at synapses to which it has bound and whether synaptic activity influences A beta synaptic binding and synaptotoxicity have remained fundamental questions. Here, we used subcellular Ca2+ imaging in rat hippocampal neurons to visualize NMDAR function at individual synapses before and after A beta application. A beta triggered a robust impairment of NMDAR Ca2+ entry at most, but not all, synapses. NMDAR function was more severely impaired at highly active synapses and synapses with bound A beta, but activity was not required for A beta synapse binding. Blocking NMDARs during A beta exposure prevented A beta-mediated impairment. Finally, A beta impaired NMDAR Ca2+ entry at doses much lower than those required for NMDAR internalization, revealing a novel, potent mode of NMDAR regulation by A beta.