mGluR5 is transiently confined in perisynaptic nanodomains to shape synaptic function

• Published in: Nature communications 2023-01, Vol.14 (1), p.244-244, Article 244
• Main Authors: Scheefhals, Nicky, Westra, Manon, MacGillavry, Harold D.
• Format: Article
• Language: English
• Subjects: 14; 14/19; 14/35; 14/63; 631/378/340; 631/378/548; 82/51; Animals; Confinement; Domains; Glutamic acid receptors (metabotropic); Humanities and Social Sciences; Image resolution; Localization; Microscopy; multidisciplinary; Neurosciences; Receptor mechanisms; Receptor, Metabotropic Glutamate 5 - physiology; Science; Science (multidisciplinary); Signaling; Synapses; Synaptic plasticity; Synaptic transmission
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35680-w

The unique perisynaptic distribution of postsynaptic metabotropic glutamate receptors (mGluRs) at excitatory synapses is predicted to directly shape synaptic function, but mechanistic insight into how this distribution is regulated and impacts synaptic signaling is lacking. We used live-cell and super-resolution imaging approaches, and developed molecular tools to resolve and acutely manipulate the dynamic nanoscale distribution of mGluR5. Here we show that mGluR5 is dynamically organized in perisynaptic nanodomains that localize close to, but not in the synapse. The C-terminal domain of mGluR5 critically controlled perisynaptic confinement and prevented synaptic entry. We developed an inducible interaction system to overcome synaptic exclusion of mGluR5 and investigate the impact on synaptic function. We found that mGluR5 recruitment to the synapse acutely increased synaptic calcium responses. Altogether, we propose that transient confinement of mGluR5 in perisynaptic nanodomains allows flexible modulation of synaptic function. The subsynaptic organization of group I mGluRs modulates their activation and downstream signaling, essential for synaptic transmission and plasticity. Here, the authors describe how the C-terminal domain of mGluR5 controls its dynamic organization in perisynaptic nanodomains, and prevents mGluR5 form entering the synapse, allowing mGluR5 to finely tune synaptic signalling.