Functional interactions between presynaptic NMDA receptors and metabotropic glutamate receptors co‐expressed on rat and human noradrenergic terminals

Abstract

Background and purpose: Electrophysiological studies described potentiation of NMDA receptor function by metabotropic glutamate receptors (mGluRs) of group I occurring postsynaptically. Since release-enhancing NMDA receptors exist on noradrenergic terminals and group I mGluRs have recently been identified on these nerve endings, we have investigated if NMDA receptor-mGluR interactions also can occur at the presynaptic level. Experimental approach: Rat hippocampus and human neocortex synaptosomes were labelled with [ 3 H]noradrenaline and superfused with mGluR agonists and antagonists. NMDA-evoked [ 3 H]noradrenaline release was produced by removal of external Mg 2 þ or by simultaneous application of NMDA and AMPA in Mg 2 þ -containing solutions. Key results: The mGluR1/5 agonist 3,5-DHPG, inactive on its own, potentiated both the release of [ 3 H]noradrenaline elicited by AMPA/NMDA/glycine and that evoked by NMDA/glycine following Mg 2 þ removal. The effect of 3,5-DHPG on the AMPA/ NMDA/glycine-induced release was insensitive to the mGluR1 antagonist CPCCOEt, but it was abolished by the mGluR5 antagonist MPEP; moreover, it was potentiated by the mGluR5 positive allosteric modulator DFB. When NMDA receptors were activated by Mg 2 þ removal, both mGluR5 and mGluR1 contributed to the evoked release, the mGluR-mediated release being blocked only by CPCCOEt and MPEP in combination. Experiments with human neocortex synaptosomes show NMDA receptor-mGluR interactions qualitatively similar to those observed in rodents. Conclusions and implications: Group I mGluRs, both of the mGluR1 and mGluR5 subtypes, co-localize with NMDA receptors on noradrenergic terminals of rat hippocampus and human neocortex. Depending on the mode of activation, NMDA receptors exert differential permissive roles on the activation of presynaptic mGluR1 and mGluR5.

Presynaptic Release-Regulating mGlu1 Receptors in Central Nervous System

“…In line with this expectation, Luccini et al (2007a) found that 3,5-DHPG significantly potentiates the releasing activity elicited by the activation of NMDA heteroreceptors on rat hippocampal noradrenergic nerve endings. In this case, however, the effect of 3,5-DHPG was prevented by the concomitant application of MPEP and CPCCOEt, while the two antagonists were inactive when added alone.…”

Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications

“…Whilst our reported reductions in mGluR5 expression in the DLPFC in ASD may be a primary aetiological process, it may also represent a secondary alteration to NMDA dysregulation, with known functional interactions existing between these two receptors (Luccini et al, 2007). Alternatively, the source of glutamatergic deficits in ASD may stem from dysregulation of pivotal molecules such as the Shank family of proteins, that also play a key role in NMDA signalling .…”

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

“…An interesting finding was the identification of functional presynaptic mGluR5s on noradrenergic terminals in the hippocampus with similar results replicated in human tissue (Luccini et al 2007). …”