Modulation by chronic stress and ketamine of ionotropic AMPA/NMDA and metabotropic glutamate receptors in the rat hippocampus.

Converging clinical and preclinical evidence has shown that dysfunction of the glutamate system is a core feature of major depressive disorder. In this context, the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has raised growing interest as fast acting antidepressant. Using the chronic mild stress (CMS) rat model of depression, performed in male rats, we aimed at analyzing whether hippocampal specific changes in subunit expression and regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or NMDA ionotropic receptors and in metabotropic glutamate receptors could be associated with behavioral vulnerability/resilience to CMS. We also assessed whether acute ketamine (10 mg/kg) was able to dampen the alterations in CMS vulnerable animals. Although chronic stress and ketamine had no effect on ionotropic glutamate receptors mRNAs (expression, RNA editing and splicing), we found selective modulations in their protein expression, phosphorylation and localization at synaptic membranes. AMPA GluA2 expression at synaptic membranes was significantly increased only in CMS resilient rats (although a trend was found also in vulnerable animals), while its phosphorylation at Ser880 was higher in both CMS resilient and vulnerable rats, a change partially dampened by ketamine. In the hippocampus from all stressed groups, despite NMDA receptor expression levels were reduced in total extract, the levels of GluN2B-containing NMDA receptors were remarkably increased in synaptic membranes. Finally, mGlu2 underwent a selective downregulation in stress vulnerable animals, which was completely restored by acute ketamine. Overall, these results are in line with a hypofunction of activity-dependent glutamatergic synaptic transmission induced by chronic stress exposure in all the animals, as suggested by the alterations of ionotropic glutamate receptors expression and localization at synaptic level. At the same time, the selective modulation of mGlu2 receptor, confirms its previously hypothesized functional role in regulating stress vulnerability and, for the first time here, suggests a mGlu2 involvement in the fast antidepressant effect of ketamine.