N-Methyl D-aspartate receptor subunit signaling in fear extinction.

N-Methyl D-aspartate receptors (NMDAR) are central mediators of glutamate actions underlying learning and memory processes including those required for extinction of fear and fear-related behaviors. Consistent with this view, in animal models, antagonists of NMDAR typically impair fear extinction, whereas partial agonists have facilitating effects. Promoting NMDAR function has thus been recognized as a promising strategy towards reduction of fear symptoms in patients suffering from anxiety disorders and post-traumatic disorder (PTSD). Nevertheless, application of these drugs in clinical trials has proved of limited utility. Here we summarize recent advances in our knowledge of NMDAR pharmacology relevant for fear extinction, focusing on molecular, cellular, and circuit aspects of NMDAR function as they relate to fear extinction at the level of behavior and cognition. We also discuss how these advances from animal models might help to understand and overcome the limitations of existing approaches in human anxiety disorders and how novel, more specific, and personalized approaches might help advance future therapeutic strategies.