Abstract
N-Methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are two major types of ionotropic glutamate receptors involved in synaptic transmission. However, excessive activity of these receptors can be cytotoxic and thus their function must be precisely controlled. We have previously reported that NMDA receptor activity is dysregulated following genetic knockout of cellular prion protein (PrPC), and that PrPC regulation of NMDA receptors is copper-dependent. Here, we employed electrophysiological methods to study NMDAR and AMPAR currents of cultured hippocampal neurons from PrPC overexpresser mice. We show that NMDA receptor current amplitude and kinetics are differentially modulated by overexpression of human or mouse PrPC. By contrast, AMPA receptor activity was unaffected. Nonetheless, AMPA receptor activity was modulated by copper ions in a manner similar to what we previously reported for NMDA receptors. Taken together, our findings reveal that AMPA and NMDA receptors are differentially regulated by PrPC, but share common modulation by copper ions.
Highlights
Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS) and interacts with both metabotropic and ionotropic receptors [1] to trigger and modulate postsynaptic responses
The N-Methyl-D Aspartate (NMDA) receptor peak current amplitude of Tga20 and wild type mice was similar across the entire range of glycine concentrations, whereas that of Tg650 was augmented at lower glycine concentrations, suggesting an overall enhancement of glycine sensitivity of NMDA receptors co-expressed with an excess of human Cellular prion protein (PrPC) (Fig. 1c)
These early findings revealed that the absence of PrPC slowed NMDA receptor deactivation and drastically augmented the magnitude of NMDA receptor mediated synaptic events, whereas α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated events showed a small enhancement of current amplitude, but no change in rise or decay times [17]
Summary
Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS) and interacts with both metabotropic and ionotropic receptors [1] to trigger and modulate postsynaptic responses. Both NMDA and AMPA receptors are critical mediators of synaptic plasticity [2–7], whereas dysregulation of these receptors contributes to neurodegeneration in a wide range of disorders, including stroke and Alzheimer’s disease [8–14]. We have previously shown that cellular prion protein (PrPC) physically interacts with, and regulates NMDA receptor function [15, 16]. AMPA receptors by PrPC, whereas both receptor types are regulated by copper ions
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