GluN2B-Containing NMDA Receptors Regulate AMPA Receptor Traffic through Anchoring of the Synaptic Proteasome

Abstract

NMDA receptors play a central role in shaping the strength of synaptic connections throughout development and in mediating synaptic plasticity mechanisms that underlie some forms of learning and memory formation in the CNS. In the hippocampus and the neocortex, GluN1 is combined primarily with GluN2A and GluN2B, which are differentially expressed during development and confer distinct molecular and physiological properties to NMDA receptors. The contribution of each subunit to the synaptic traffic of NMDA receptors and therefore to their role during development and in synaptic plasticity is still controversial. We report a critical role for the GluN2B subunit in regulating NMDA receptor synaptic targeting. In the absence of GluN2B, the synaptic levels of AMPA receptors are increased and accompanied by decreased constitutive endocytosis of GluA1-AMPA receptor. We used quantitative proteomic analysis to identify changes in the composition of postsynaptic densities from GluN2B Ϫ/Ϫ mouse primary neuronal cultures and found altered levels of several ubiquitin proteasome system components, in particular decreased levels of proteasome subunits. Enhancing the proteasome activity with a novel proteasome activator restored the synaptic levels of AMPA receptors in GluN2B Ϫ/Ϫ neurons and their endocytosis, revealing that GluN2B-mediated anchoring of the synaptic proteasome is responsible for fine tuning AMPA receptor synaptic levels under basal conditions.

Perturbation of Ephrin Receptor Signaling and Glutamatergic Transmission in the Hypothalamus in Depression Using Proteomics Integrated With Metabolomics

“…The disturbance of glutamatergic transmission and its related dysfunction of synaptic plasticity have been speculated as the underlying mechanisms of depression (Ferreira et al, 2015;Francija et al, 2018). Our integrated network analysis also predicted that the EPHB2 and EFNB1 interactions play an important role in regulating NMDARs (Figure 5).…”

“…Regarding glutamatergic receptors, recent reports have demonstrated that alterations of NMDAR subunits mediate synaptic plasticity impairment in the PFC and hippocampus of LPS-induced depression mice (Walker et al, 2013;Francija et al, 2018). NMDARs, comprising GluN1, GluN2A and 2B, and GluN3 subunits, have particular features, such as the detectors of coincident presynaptic and postsynaptic activities (Ferreira et al, 2015). The hypothalamus mRNA level of GluN1 in LPS mice was significantly increased even with no significant change in its protein expression.…”

PKMζ Inhibition Disrupts Reconsolidation and Erases Object Recognition Memory

“…4B; test AD: t (16) ϭ 3.430, p ϭ 0.0034; test CD: t (16) ϭ 3.084, p ϭ 0.0071). Conversely, post-RA intra-CA1 infusion of DYN (120 pmol/l), a cell-permeable dynamin inhibitor that impedes AMPAR internalization (Ferreira et al, 2015) and increases GluA1 and GluA2 expression in a CSF enriched in synapticassociated proteins (Fig. 4C, left, GluA1: t (3) ϭ 3.879, p ϭ 0.0303 for VEH vs DYN; GluA2: t (3) ϭ 6.635, p ϭ 0.007 for VEH vs DYN; right, t (2) ϭ 8.217, p ϭ 0.014 for HT vs CSF), reversed the amnesia caused by ZIP ( Fig.…”

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“…Synaptic localization of the proteasome, in turn, promotes PSD protein degradation (Bingol & Schuman ), regulates neurotransmitter receptor trafficking (Ferreira et al . ), and plays important roles in shaping structural and functional plasticity (Djakovic et al . ; Hamilton et al .…”