Activity Regulates the Synaptic Localization of the NMDA Receptor in Hippocampal Neurons

Abstract

We describe here a novel effect of activity on the subcellular distribution of NMDA receptors in hippocampal neurons in culture. In spontaneously active neurons, NMDA receptors were clustered at a few synaptic and nonsynaptic sites. Chronic blockade of NMDA receptor activity induced a 380% increase in the number of NMDA receptor clusters and a shift to a more synaptic distribution. This effect was reversible. The distributions of the presynaptic marker synaptophysin, the AMPA-type glutamate receptor subunit GluR1, and the putative NMDA receptor clustering protein PSD-95 were not affected by blockade. Regulation of the synaptic localization of NMDA receptors by activity may define a novel mechanism by which input controls a neuron's ability to modify its synapses.

In vivo blockade of N-methyl-d-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex

“…It is not surprising that our results differ from the above mentioned and other physiological findings that may have overlooked the changes in silent synapses (e.g. see ref Quinlan et al, 1999) or the biochemical measurements that, like our light microscopic analyses, examines changes that are averaged over larger volumes (Rao and Craig, 1997;Williams et al, 1998;Grosshans et al, 2002).…”

“…Malenka and Nicoll, 1999). In vitro and fewer in vivo preparations have been used to demonstrate that NMDA receptors, too, are removed from or inserted into synaptic membrane (Rao and Craig, 1997;Liao et al, 1999;Quinlan et al, 1999;Heynen et al, 2000;Barria and Malinow, 2002;Grosshans et al, 2002;Tovar and Westbrook, 2002). However, since nearly all of these studies have used neonatal tissues, whether or not such dynamic properties of NMDA receptor subunits persist at mature synapses, in vivo, is a topic that remains relatively unexplored.…”

“…NR2B subunits are known to be rapidly internalized in immature neurons (Roche et al, 2001). Activity-dependent trafficking of synaptic NR2B-containing receptors has been shown anatomically using in vitro fluorescent preparations (Rao and Craig, 1997), electrophysiologically (Tovar and Westbrook, 2002), and biochemically (Grosshans et al, 2002). While none of these methods or our EM-ICC have examined single synapse over time, a decrease consistent across a large population of synapses supports the idea that there is a mechanism for NR2B subunits to be trafficked out of the D-APV treated synapses.…”

“…Only a few other studies have examined trafficking of NR2B subunits following NMDA receptor blockade of varying durations. Both Tovar and Westbrook (2002) and Rao and Craig (1997) demonstrated that inactivation of NMDA receptors results in an elevation of NMDA receptors at synapses, with no preference between NR2A-and NR2B-containing receptors. On the other hand, Barria and Malinow (2002) showed that while NR2A subunits are trafficked into the spine after D-APV treatment, NR2B subunits are not affected by it.…”

Adaptive plasticity of NMDA receptors and dendritic spines: Implications for enhanced vulnerability of the adolescent brain to alcohol addiction

“…This occurs via regulation of NMDA receptor trafficking, a generic term for movement between different cellular domains such as the ER, golgi, endosomes, and various microdomains on the cell surface including the synapse (Perez-Otano and Ehlers, 2005). Homeostatic enhancement of NMDA receptor clustering at the synapse has also been observed following chronic inhibition of synaptic activity or direct inhibition of NMDA receptors (Rao and Craig, 1997). These changes are undoubtedly the result of alterations in NMDA receptor trafficking.…”