AMPA GluR-A receptor subunit mediates hippocampal responsiveness in mice exposed to stress

Because stress represents a major recipitating event for psychiatric disorders, it is important to identify molecular mechanisms that may be altered in vulnerable individuals when exposed to stress. Here, we studied GluR−A2/2 mice, animals with compromised AMPA receptor signaling, and characterized by a schizophrenic as well as depressive phenotype to investigate changes occurring in response to an acute stress. Wild−type and GluR−A2/2 mice were exposed to a single immobilization stress and sacrificed immediately after the end of the stress for the analysis of activity regulated genes and of glutamatergic synapse responsiveness. The acute stress produced a marked increase in the hippocampal expression of Arc (activity−regulated cytoskeletal−associated protein) in GluR−A2/2, but not in wild−type mice, which was associated with a similar increase of phospho−CaMKII, a partner in the action of Arc. When looking at the glutamatergic response to stress in wild−type animals, we found that stress increased GluR−A phosphorylation on serine831, an effect that was paralleled by a significant increase of the phosphorylation of the main NMDA receptor subunits, that is, NR−1 and NR−2B. Conversely, the stress−induced modulation of NMDA receptor subunits was not observed in GluR−A2/2 mice. We suggest that enhanced stress responsiveness in GluR−A2/2 mice may be due, at least in part, to their inability to activate NMDA−mediated glutamatergic neurotransmission, suggesting that the integrity of AMPA/NMDA receptor function may be important for successful coping under stressful condition