Stimulation of N‐methyl‐d‐aspartate receptors, AMPA receptors or metabotropic glutamate receptors leads to rapid internalization of AMPA receptors in cultured nucleus accumbens neurons

Abstract

In hippocampus and other regions, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors are inserted into synapses during long-term potentiation and removed during long-term depression. However, little is known about regulation of AMPA receptor trafficking in the nucleus accumbens (NAc), despite growing evidence that glutamate-dependent forms of plasticity in the NAc contribute to drug addiction. Using postnatal rat NAc cultures and an immunocytochemical method that selectively detects newly internalized GluR1, we studied the regulation of AMPA receptor internalization in NAc neurons by glutamate agonists. Newly internalized GluR1 was detected during 15 or 30 min of incubation at room temperature, indicating a basal rate of GluR1 turnover. The rate of GluR1 internalization was increased by glutamate (50 microM) within 5 min of its addition. Glutamate-induced GluR1 internalization was partially blocked by either an AMPA receptor antagonist (CNQX; 20 microM) or an N-methyl-D-aspartate (NMDA) receptor antagonist (APV; 50 microM). Both NMDA (50 microM) and AMPA (50 microM) increased GluR1 internalization in a Ca(2+)-dependent manner. The NMDA effect was blocked by APV while the AMPA effect was blocked by APV or CNQX. We interpret these findings to suggest that NMDA and AMPA ultimately trigger GluR1 internalization through the same NMDA receptor-dependent pathway. The effect of glutamate was also partially blocked by the group 1 metabotropic glutamate receptor antagonist N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC; 50 microM), while the group 1 agonist 3,5-dihydroxyphenylglycine (DHPG; 50 microM) stimulated GluR1 internalization. These data suggest that AMPA receptors on NAc neurons may be subject to rapid regulation of their surface expression in response to changes in the activity of glutamate inputs from cortical and limbic regions.

Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction

“…Calcium-dependent electrical activity in Xenopus spinal neurons homeostatically regulates specification of acetylcholine (ACh), glutamate, GABA, and glycine at early stages of development (1), depolarization increases the proportion of dopaminergic neurons in nodose, petrosal, and dorsal root rat ganglia (2), and specification of GABAergic and glutamatergic phenotypes in developing hippocampal rat granule cells depends on electrical activity (3). NMDA receptor (NMDAR) expression is modulated by early activity in the rat superior colliculus (4) and in cat and ferret visual cortex (5), and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) levels are activity-dependent in postnatal rat nucleus accumbens neurons (6). Kainate receptor expression depends on activity in postnatal rat thalamocortical synapses (7).…”

Novel Blockade of Protein Kinase A-Mediated Phosphorylation of AMPA Receptors

“…Although not described as of yet, alterations in protein associations within this complex could serve to prevent PKA access to GluR1. Other reports have demonstrated that glutamatergic activity via both AMPAR and NMDAR regulates trafficking of GluR1-containing AMPARs (Carroll et al, 1999;Beattie et al, 2000;Ehlers, 2000;Mangiavacchi and Wolf, 2004), and movement of GluR1 to distinct subcellular compartments could also potentially serve to uncouple PKA from GluR1. However, NMDAR-mediated endocytosis of GluR1 is a Ca 2ϩ -and phosphatase-dependent event.…”

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

“…In contrast, the effect of the more selective Ro 25-6981 on the acquisition of conditioned fear or synaptic plasticity in the amygdala is currently unknown. In addition, AMPA receptor endocytosis occurs downstream of NMDA receptor activation in the induction of LTD (Ahmadian et al, 2004;Mangiavacchi and Wolf, 2004;Moult et al, 2006). Accordingly, activation of NMDA NR2B receptors would be expected to affect a number of different cellular processes, in addition to mediating AMPA receptor endocytosis.…”