Presynaptic metabotropic glutamate receptors (mGluRs) are essential for activity-dependent modulation of synaptic transmission in the brain. However, the mechanism 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 group II mGluR2 localized diffusely along the axon and boutons, and is highly mobile, while the group III mGluR7 was 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 was modulated by intracellular interactions. In contrast, immobilization of mGluR7 at the active zone was mediated by its extracellular domain that interacts in trans with the postsynaptic adhesion molecule ELFN2. Moreover, we found that receptor activation or changing synaptic activity did not alter the surface mobility of presynaptic mGluRs. Additionally, computational modeling of presynaptic mGluRs activity revealed that the precise subsynaptic localization of mGluRs control 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.
bioRxiv Subject Collection: Neuroscience