Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning

Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal learning, suggesting that mGluR5 signaling is required for different forms of adaptive learning. Here, we tested whether ADX47273, a selective positive allosteric modulator (PAM) of mGluR5, can enhance adaptive learning in mice. We found that systemic administration of the ADX47273 enhanced reversal learning in the Morris Water Maze, an adaptive task. In addition, we found that ADX47273 had no effect on single-session and multi-session extinction, but administration of ADX47273 after a single retrieval trial enhanced subsequent fear extinction learning. Together these results demonstrate a role for mGluR5 signaling in adaptive learning, and suggest that mGluR5 PAMs represent a viable strategy for treatment of maladaptive learning and for improving behavioral flexibility. The ability of animalsto adapt their behaviorsto a changing environment is essential for survival. Acquisition of new memories and behavioral flexibility is inherently linked to enable the organism to modify its response to novel information. To study the biological underpinnings of adaptive learning, a number of behavioral models have been established that have enabled us to better understand the circuits and molecular mechanisms involved. One of the most prominent models of adaptive learning is fear extinction in which a previously conditioned aversive memory can be suppressed or extinguished by repeated presenta