Selective Recruitment of Presynaptic and Postsynaptic Forms of mGluR-LTD

Abstract

In area CA1 of the hippocampus, long-term depression (LTD) can be induced by activating group I metabotropic glutamate receptors (mGluRs), with the selective agonist DHPG. There is evidence that mGluR-LTD can be expressed by either a decrease in the probability of neurotransmitter release [P(r)] or by a change in postsynaptic AMPA receptor number. However, what determines the locus of expression is unknown. We investigated the expression mechanisms of mGluR-LTD using either a low (30 μM) or a high (100 μM) concentration of (RS)-DHPG. We found that 30 μM DHPG generated presynaptic LTD that required the co-activation of NMDA receptors, whereas 100 μM DHPG resulted in postsynaptic LTD that was independent of the activation of NMDA receptors. We found that both forms of LTD occur at the same synapses and that these may constitute the population with the lowest basal P(r). Our results reveal an unexpected complexity to mGluR-mediated synaptic plasticity in the hippocampus.

Amyloid-β1–42oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C3aR/C5aR signaling

“…Despite these important advances, how NMDARs and mGluRs, individually or synergistically, are involved in triggering synaptic weakening and loss in AD is poorly understood. Of relevance to the present study, at least two distinct forms of DHPG-LTD exist, which can be distinguished by the dependence on NMDARs (Palmer, Irving, Seabrook, Jane, & Collingridge, 1997; Sanderson, et al, 2022). In our current study, DHPG-LTD under control conditions was not affected by NMDAR antagonism.…”

“…There are two distinct forms of DHPG-LTD that can be distinguished by their dependence upon the activation of NMDARs (Palmer, Irving, Seabrook, Jane, & Collingridge, 1997; Sanderson, et al, 2022). To determine whether NMDARs are required for either mGlu 5 R-LTD under control conditions or the enhanced mGlu 5 R-LTD observed in the presence of oAβ, we used a selective NMDAR antagonist, L689,560.…”

Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling

“…There are two distinct forms of DHPG-LTD that can be distinguished by their dependence upon the activation of NMDARs. 46 , 51 To determine whether NMDARs are required for mGlu 5 R-LTD either under control conditions or the enhanced mGlu 5 R-LTD observed in the presence of oAβ, we used a selective NMDAR antagonist, L689,560 (5 μM). L689,560 was chosen as it acts at the glycine site of the NMDAR and so is independent of L-glutamate concentration, which might be altered by oAβ treatment.…”

Loss of synaptopodin impairs mGluR5 and protein synthesis–dependent mGluR-LTD at CA3-CA1 synapses

“…Spines harboring SP and SA support synaptic plasticity, as demonstrated by the findings that SPKO mice show impaired LTP ( 21 , 25 , 65 ) and mGluR-LTD ( 27 ). The locus of expression for mGluR-LTD can be influenced by various factors including hippocampus development, aging, subregion, and experimental protocol ( 14 , 43 , 66 , 67 ). In this study, we show for the first time that SP, a postsynaptic protein, controls the locus of expression of mGluR-LTD.…”