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

Abstract

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.