Activation of Group II Metabotropic Glutamate Receptors Promotes LTP Induction at Schaffer Collateral-CA1 Pyramidal Cell Synapses by Priming NMDA Receptors

Abstract

It is well established that selective activation of group I metabotropic glutamate (mGlu) receptors induces LTD of synaptic transmission at Schaffer collateral-CA1 synapses. In contrast, application of 1S,3R-ACPD, a mixed agonist at group I and group II mGlu receptors, induces LTP. Using whole-cell recordings from CA1 pyramidal cells and field recordings in the hippocampal CA1 region, we investigated the specific contribution of group II mGlu receptors to synaptic plasticity at Schaffer collateral-CA1 synapses in acute slices of adult mice. Pharmacological activation of group II mGlu receptors (mGlu2 and mGlu3 receptors) with the specific agonist LY354740 in conjunction with electrical stimulation induced postsynaptic LTP. This form of plasticity requires coactivation of NMDA receptors (NMDARs). Group II mGlu receptor activation led to PKC-dependent phosphorylation of the GluN1 subunit. We found that both synaptic and extrasynaptic NMDARs, which are differentially modulated by mGlu2 and mGlu3 receptors, contribute to LTP induction. Furthermore, LTP initiated by activation of group II mGlu receptors was not occluded by LTP induced with high-frequency trains of stimuli. However, the phosphorylation of NMDARs mediated by group II mGlu receptor activation led to a priming effect that enhanced subsequent high-frequency stimulation-induced LTP. These findings reveal a novel metaplastic mechanism through which group II mGlu receptors modulate synaptic function at the Schaffer collateral input to CA1 pyramidal cells, thereby lowering the threshold to induce plasticity.

Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo

“…Co-activation of mGlu5Rs with NMDARs located in this vicinity is known to strongly enhance the function of the NMDARs 24 – 26 . Group II mGluRs also are located perisynaptically 27 , can enhance NMDA-evoked currents 28 , 29 , and have been implicated in the induction/maintenance of LTD 30 – 32 . However, unlike mGlu5Rs, they do not appear to have a role during LTD induction by LFS in vivo .…”

Metabotropic glutamate receptor subtype 3 gates acute stress-induced dysregulation of amygdalo-cortical function

“…Canonical plasticity induced by mGlu 2/3 involves a decrease in presynaptic release probability 41 – 45 , and recent publications have shown that activation of mGlu 2/3 can modify postsynaptic NMDAR receptor function under some circumstances 46 , 47 . However, the present data provide direct evidence that activation of mGlu 3 induces LTD by postsynaptic AMPAR internalization in PFC pyramidal cells, similar to the mechanism by which mGlu 5 -LTD occurs in the hippocampus and nucleus accumbens 48 , 49 .…”

Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert

“…However, recent studies support the notion that NMDARs can be downstream effectors of G i/o -coupled mGluRs. For example, mGluR7 can downregulate NMDARs through an actin-dependent mechanism (Gu et al, 2012), and agonists of mGluR2 and 3 can potentiate NMDARs via kinase-mediated pathways (Rosenberg et al, 2016). Unfortunately, limited studies have addressed the effects of group II and III mGluR activation on AMPARs or KARs.…”