Inhibiting mGluR5 activity by AFQ056/Mavoglurant rescues circuit-specific functional connectivity in Fmr1 knockout mice

ABSTRACT Previous work has demonstrated that neuroimaging biomarkers which capture functional connectivity of the brain can be used to define a specific and robust endophenotype in Fmr1‐/y mice, a well‐established animal model of human Fragile‐X Syndrome (FXS). However, it is currently unknown whether this macroscopic measure of brain connectivity is sufficiently sensitive to reliably detect changes caused by pharmacological interventions. Here we inhibited the activity of the metabotropic glutamate receptor‐5 (mGluR5) using AFQ056/Mavoglurant, a drug that is assumed to normalize excitatory/inhibitory neural signaling imbalances in FXS. We employed resting‐state‐fMRI (rs‐fMRI) and diffusion‐weighted imaging (DWI) to test whether Mavoglurant re‐established brain connectivity ‐ at least partly ‐ within some of the affected circuits in Fmr1‐/y mice that are related to social behavior deficits. In line with previous findings, we observed that Fmr1‐/y mice exhibited impaired social interaction, reduced connectivity in three main functional networks and altered network topology. At the group level, Mavoglurant did neither rescue abnormal social behavioral nor white matter abnormalities; however, for some, but not all of these circuits Mavoglurant had a genotype‐specific effect of restoring functional connectivity. These results show that rs‐fMRI connectivity is sufficiently sensitive to pick up system‐level changes after the pharmacological inhibition of mGluR5 activity. However, our results also show that the effects of Mavoglurant are confined to specific networks suggesting that behavioral benefits might be restricted to narrow functional domains.