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

Because stress represents a major precipitating 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‐A^?/? 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‐A^?/? 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‐A^?/?, 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‐A^?/? mice. We suggest that enhanced stress responsiveness in GluR‐A^?/? 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 conditions. © 2010 Wiley‐Liss, Inc.