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

## TL;DR

This study investigates how the interaction between mGlu7 and ELFN1 proteins affects the effectiveness of drugs that modulate mGlu7 in the brain.

## Contribution

The study reveals that ELFN1 does not significantly alter the efficacy of mGlu7 negative modulators but reduces the maximal effect of positive modulators.

## Key findings

- ELFN1 presence does not change the efficacy of mGlu7 negative allosteric modulators.
- Positive allosteric modulators show reduced maximal potentiation in the presence of ELFN1.
- mGlu7 modulators retain activity at synapses where ELFN1 is expressed.

## Abstract

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.