Control of Theta Oscillatory Activity Underlying Fear Expression by mGlu₅ Receptors

Metabotropic glutamate 5 receptors (mGlu₅) are thought to play an important role in mediating emotional information processing. In particular, negative allosteric modulators (NAMs) of mGlu₅ have received a lot of attention as potential novel treatments for several neuropsychiatric diseases, including anxiety-related disorders. The aim of this study was to assess the influence of pre- and post-training mGlu₅ inactivation in cued fear conditioned mice on neuronal oscillatory activity during fear retrieval. For this study we used the recently developed mGlu₅ NAM Alloswicth-1 administered systemically. Injection of Alloswicth-1 before, but not after, fear conditioning resulted in a significant decrease in freezing upon fear retrieval. Mice injected with Alloswicth-1 pre-training were also implanted with recording microelectrodes into both the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC). The recordings revealed a reduction in theta rhythmic activity (4-12 Hz) in both the mPFC and vHPC during fear retrieval. These results indicate that inhibition of mGlu₅ signaling alters local oscillatory activity in principal components of the fear brain network underlying a reduced response to a predicted threat.