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

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

Significance statement

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

SUBMITTER: Sinnen BL 

PROVIDER: S-EPMC5125218 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature