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.
This research was funded by the Austrian Science Found grant NR W012060-10 to F.F and by the Dr. Helmut Legerlotz-Stiftung GZ76130 to A.R.-P. Funding by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe, European Union (projects I+D+i CTQ2017-89222-R and PID2020-120499RB-I00), by the Catalan government (2017 SGR 1604) to A.L. European Union’s Horizon 2020 research and innovation program under Marie Skłodowska-Curie grant agreement No. 801342 (Tecniospring INDUSTRY, TECSPR19-1-0062) and the Government of Catalonia’s Agency for Business Competitiveness (ACCIÓ) to X.G. Open Access Funding by the Austrian Science Fund (FWF).