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,