An Appraisal of the Influence of the Metabotropic Glutamate 5 (mGlu5) Receptor on Sociability and Anxiety

Amongst the many neurotransmitter systems causally linked to the expression of social behavior, glutamate appears to play a pivotal role. In particular, metabotropic glutamate 5 (mGlu5) receptors have received much attention as its altered function has been reported in several mouse models of autism spectrum disorders and mental retardation. Inhibition of the activity of mGlu5 receptors by means of genetic or pharmacological manipulations improved social deficits in some of these animal models. However, in normal wild-type (WT) mice, pharmacological blockade of mGlu5 receptors yielded inconsistent results. The aim of our study was to investigate the actual contribution of decreased or absent mGlu5 receptor function in sociability and anxiety-like behavior as well as to explore the impact of mGlu5 receptor ablation on the pattern of brain activation upon social exposure. Here we show that Grm5-/- mice display higher social preference indexes compared to age-matched WT mice in the three-chambered social task. However, this effect was accompanied by a decreased exploratory activity during the test and increased anxiety-like behavior. Contrary to mGlu5 receptor ablation, the mGlu5 receptor negative allosteric modulator 3-((2-methyl-1,4-thiazolyl)ethynyl)pyridine (MTEP) induced anxiolytic effects without affecting social preference in WT mice. By mapping c-Fos expression in 21 different brain regions known to be involved in social interaction, we detected a specific activation of the prefrontal cortex and dorsolateral septum in Grm5-/- mice following social interaction. C-Fos expression correlation-based network and graph theoretical analyses further suggested dysfunctional connectivity and disruption of the functional brain network generated during social interaction in Grm5-/- mice. The lack of mGlu5 receptors resulted in profound rearrangements of the functional impact of prefrontal and hippocampal regions in the social interaction network. In conclusion, this work reveals a complex contribution of mGlu5 receptors in sociability and anxiety and points to the importance of these receptors in regulating brain functional connectivity during social interaction.