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

Beta amyloid (Aβ) triggers the elimination of excitatory synaptic connections in the CNS, an early manifestation of Alzheimer's disease. Oligomeric assemblies of Aβ peptide associate with excitatory synapses resulting in synapse elimination through a process that requires NMDA-type glutamate receptor activation. Whether Aβ affects synaptic NMDA receptor (NMDAR) function directly and acts locally at synapses to which it has bound and whether synaptic activity influences Aβ 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 Aβ application. Aβ 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 Aβ, but activity was not required for Aβ synapse binding. Blocking NMDARs during Aβ exposure prevented Aβ-mediated impairment. Finally, Aβ impaired NMDAR Ca2+ entry at doses much lower than those required for NMDAR internalization, revealing a novel, potent mode of NMDAR regulation by Aβ.

SIGNIFICANCE STATEMENT: Amyloid β (Aβ) is strongly implicated in Alzheimer's disease. Aβ triggers the elimination of excitatory synapses through a mechanism that requires NMDA receptors (NMDARs). However, little is known about how or whether Aβ influences synaptic NMDAR function. We used an imaging-based assay to investigate the relationship among Aβ binding, activity, and NMDAR function at individual synapses. Aβ 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 Aβ. Blocking NMDARs during Aβ exposure prevented Aβ-mediated impairment. Together, our experiments reveal a novel use-dependent, potent, and local mode of Aβ-mediated NMDAR impairment.