Reconsideration of mGlu5 and NMDA functions
Our study highlights the crucial role of membrane potential in modulating the activity of mGlu5 receptors, which are involved in synaptic transmission, plasticity, and metaplasticity. We found that mGlu5 receptors are fully active at resting membrane potentials, but their activity is dampened upon depolarization. This sensitivity to Vm is highly relevant given that neuronal activity can cause fluctuations in Vm. Additionally, our study suggests that the optimal functioning of mGlu5 receptors at resting membrane potential may potentiate NMDA receptors too. Traditionally, NMDA receptors are known to be “coincidence detectors” of pre- and post-synaptic activation because they are blocked by the Mg2+ ion at resting potential . However, our results indicate that they may also play an unexpected role at resting potential, facilitated by the permissive effect of mGlu5 receptors. Recent measurements of interstitial fluid composition in vivo show that the actual Mg2+ concentrations (0.7 – 0.8 mM. ) are lower than those used experimentally, which may underestimate the functional importance of NMDA receptors at resting potential . Our findings add complexity to the functional cross-talk between mGlu5 and NMDA receptors, with mGlu5 acting as a starter for NMDA receptor activation on recently resting neurons. Once the membrane potential is depolarized enough to unblock NMDA receptors, they can function autonomously, while negative feedback from Vm on mGlu5 receptors limits NMDA facilitation and synapse overexcitability. This finding is likely to have significant implications for the nature of induced neuronal plasticity, which relies on the concerted activities of mGlu5 and NMDA receptors . Different cellular mechanisms for inducing plasticity will come into play depending on the type of activatable receptor following network activity.
The acute effect of depolarization on the activity and signaling of mGlu5 receptors adds to the extensive regulation of protein complexes around these receptors and their functional interactions that are regulated by neuronal activity. The mGlu5 receptor has been proposed as a homeostatic regulator of synaptic transmission, a role that requires activity-induced monomeric Homer1a expression . Within the neuronal environment, the function of mGlu5 receptors is dynamically regulated by interactions with multimeric Homer proteins, which is dampened by the monomeric Homer1a protein during sustained synaptic activity . Our team recently demonstrated an instantaneous disruption of the mGlu5-Homer interaction following membrane depolarization in hippocampal neurons , which cannot be explained by the induction of monomeric Homer1a synthesis, a process taking place several minutes later. This depolarization-dependent disruption occurs even if NMDA receptors are blocked and may be attributed to the direct sensitivity of the mGlu5 receptor to membrane potential, as demonstrated in this study. However, testing this hypothesis would require knowledge of and mutations to the voltage sensor of the mGlu5 receptor without affecting the receptor’s response to its ligand.
Following the induction of a first plasticity event, the expression of Homer1a blocks the activity of the mGlu5 and NMDA receptors to prevent the induction of subsequent plasticity, allowing cellular signaling required for the expression of the engaged plasticity and the maintenance of the neuron in the functional network in which it has been committed . It is worth noting that the direct effect of Vdepol on mGlu5 receptor functioning described in this study is similar to the effect of Homer1a, which inhibits canonical receptor signaling. The acute effect of depolarization is likely to control the function of the mGlu5 receptor on a shorter time scale. The decreased affinity of the receptor for multimeric Homer, first by membrane depolarization (seconds) and then by CamKII-dependent Homer phosphorylation (minutes, ), would promote decreased competition and enable the interaction with monomeric Homer1a once this protein is expressed (20-30 minutes, ), enabling long-lasting plasticity.
The mGlu5 receptor senses moderate Vm variations,