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.
Fumagalli
Fabio
F
Center of Neuropharmacology, Department of Pharmacological Sciences, Università degli Studi di Milano, Milan, Italy.
Caffino
Lucia
L
Vogt
Miriam A
MA
Frasca
Angelisa
A
Racagni
Giorgio
G
Sprengel
Rolf
R
Gass
Peter
P
Riva
Marco Andrea
MA
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013312:Stress, Physiological; D016704:Synapsins / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003598:Cytoskeletal Proteins; D005938:Glucocorticoids; D018698:Glutamic Acid; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016704:Synapsins; C092069:activity regulated cytoskeletal-associated protein