Long-term depression is independent of GluN2 subunit composition

Abstract

NMDA receptors (NMDARs) mediate major forms of both long-term potentiation (LTP) and long-term depression (LTD) and understanding how a single receptor can initiate both phenomena remains a major question in neuroscience. A prominent hypothesis implicates the NMDAR subunit composition, specifically GluN2A and GluN2B, in dictating the rules of synaptic plasticity. However, studies testing this hypotheses have yielded inconsistent and often contradictory results, especially for LTD. These inconsistent results may be due to challenges in the interpretation of subunit-selective pharmacology and in dissecting out the contributions of differential channel properties versus the interacting proteins unique to GluN2A or GluN2B. In this study, we address the pharmacological and biochemical challenges by utilizing a singleneuron genetic approach to delete NMDAR subunits in both male and female conditional knock-out mice. In addition, emerging evidence that non-ionotropic signaling through the NMDAR is sufficient for NMDAR-dependent LTD allowed the rigorous assessment of unique subunit contributions to NMDAR-dependent LTD while eliminating the variable of differential charge transfer. Here we find that neither the GluN2A nor the GluN2B subunit is strictly necessary for either non-ionotropic or ionotropic LTD.peer-reviewed)

Increased excitation-inhibition balance due to a loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

“…Neonatal [P0-P1] SR fl mice of both sexes were stereotaxically injected with high-titer rAAV1-Cre:GFP viral stock (~1-5 x 10 12 vg/mL) with coordinates targeting hippocampal CA1 as previously described (Gray et al, 2011;Wong and Gray, 2018). At 2-3 months, the injected mice were anesthetized with isoflurane and transcardially perfused with ice-cold artificial cerebrospinal fluid (ACSF), containing (in mM) 119 NaCl, 26.2 NaHCO3, 11 glucose, 2.5 KCl, 1 NaH2PO4, 2.5 CaCl2, and 1.3 MgSO4.…”

Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling in Dendritic Spine Shrinkage

“…Recent studies have demonstrated that NMDAR-dependent LTD and spine shrinkage can occur independent of ion flux through the NMDAR. Several of these studies have shown that LTD and spine shrinkage induced by low-frequency glutamatergic stimulation are blocked by competitive glutamate binding site NMDAR antagonists, but persist in the presence of the glycine/Dserine binding site NMDAR antagonist 7-chlorokynurenate (7-CK) or the pore blocker MK-801 (Nabavi et al, 2013;Stein et al, 2015;Carter and Jahr, 2016;Wong and Gray, 2018); but, it is important to note that other studies find contradictory results (Babiec et al, 2014;Volianskis et al, 2015;Sanderson et al, 2016). Furthermore, high-frequency glutamatergic stimulation that normally leads to LTP and spine growth instead has been found to drive LTD and spine shrinkage when ion flow through the NMDAR is blocked with 7-CK or MK-801 (Nabavi et al, 2013;Stein et al, 2015).…”

Non-ionotropic NMDA receptor signaling gates bidirectional structural plasticity of dendritic spines

“…Ion flow-independent NMDAR signaling has been implicated by many independent studies in spine shrinkage and synaptic weakening (Nabavi et al, 2013;Aow et al, 2015;Birnbaum et al, 2015;Stein et al, 2015;Carter and Jahr, 2016;Wong and Gray, 2018;Stein et al, 2020;Thomazeau et al, 2020). Here, we made the unexpected discovery that this non-ionotropic NMDAR signaling pathway is also required for spine growth during synaptic strengthening.…”

“…Glutamate binding to NMDARs initiates a signaling cascade that drives synaptic weakening (LTD) and the shrinkage of dendritic spines (sLTD), even when ion flow is blocked pharmacologically (Nabavi et al, 2013;Stein et al, 2015;Carter and Jahr, 2016;Wong and Gray, 2018). Furthermore, in the absence of ion flux, patterns of glutamatergic stimulation that would normally drive LTP and spine growth, instead drive LTD and spine shrinkage (Nabavi et al, 2013;Stein et al, 2015;Stein et al, 2020).…”

“…Recent studies have demonstrated that LTD (Nabavi et al, 2013;Carter and Jahr, 2016;Wong and Gray, 2018) and dendritic spine shrinkage (Birnbaum et al, 2015;Stein et al, 2015;Thomazeau et al, 2020) can occur independent of ion flux through the NMDA receptor. These findings have supported a model in which glutamate binding leads to conformational changes in the NMDAR that drive spine shrinkage and synaptic weakening.…”