Subsynaptic mobility of presynaptic mGluR types is differentially regulated by intra- and extracellular interactions

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Presynaptic metabotropic glutamate receptors (mGluRs) are essential for activity-dependent modulation of synaptic transmission in the brain. However, the mechanisms that control the subsynaptic distribution and mobility of these receptors to contribute to their function are poorly understood. Here, using super-resolution microscopy and single-molecule tracking, we provide novel insights in the molecular mechanisms that control the spatial distribution and mobility of presynaptic mGluRs. We demonstrate that mGluR2 localizes diffusely along the axon and boutons and is highly mobile, while mGluR7 is immobilized specifically at the active zone, indicating that distinct mechanisms underlie the dynamic distribution of these receptor types. Indeed, we found that the positioning of mGluR2 is modulated by intracellular interactions. In contrast, immobilization of mGluR7 at the active zone is mediated by its extracellular domain that interacts in <jats:italic>trans</jats:italic> with the postsynaptic adhesion molecule ELFN2. Moreover, we found that receptor activation or changing synaptic activity does not alter the surface mobility of presynaptic mGluRs. Additionally, computational modeling of presynaptic mGluRs activity revealed that the precise subsynaptic localization of mGluRs determines their activation probability and thus directly impacts their ability to modulate neurotransmitter release. Altogether, this study demonstrates that distinct mechanisms control surface mobility of presynaptic mGluRs to differentially contribute to the regulation of glutamatergic synaptic transmission.</jats:p>