Profiling the Impact of mGlu₇/Elfn1 Protein Interactions on the Pharmacology of mGlu₇ Allosteric Modulators

The group III metabotropic glutamate receptors (mGlu receptors) are predominantly expressed presynaptically throughout the central nervous system (CNS) where they regulate the release of glutamate and GABA. These receptors have recently been shown to be anchored by transsynaptic expression of the laminin proteins ELFN1 and ELFN2. In particular, the mGlu₇ receptor is localized at presynaptic active zones from pyramidal cells to somatostatin-containing interneurons with postsynaptic ELFN1, and this interaction drives the rapidly facilitating nature of these synapses in the hippocampus and cortex. Interestingly, individuals with mutations in ELFN1 or GRM7 genes present with attention-deficit hyperactivity disorder and epilepsy, and knockout mice of each of these proteins develop seizures with very similar time courses. In the current manuscript, we explore the hypothesis that the pharmacology of positive and negative allosteric modulators (PAMs and NAMs) of mGlu₇ might be changed in the presence of ELFN1. These results showed that, across a range of NAMs, we observed similar efficacy in the presence of ELFN1. For PAMs, we observed decreased maximal potentiation when ELFN1 was present, but all examined compounds were still able to potentiate receptor signaling regardless of ELFN1 expression. Finally, we confirm that a tool PAM with mGlu₇ activity is able to potentiate responses at pyramidal cell-somatostatin interneuron synapses where ELFN1 is expressed. These results suggest that, for the modulators shown here, native tissue activity should be retained in the presence of ELFN1 expression.