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

J. S. Ferreira, J. Schmidt, P. Rio, R. Aguas, A. Rooyakkers, K. W. Li, A. B. Smit, A. M. Craig, A. L. Carvalho
Journal of Neuroscience. 2015-06-03; 35(22): 8462-8479
DOI: 10.1523/JNEUROSCI.3567-14.2015

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1. J Neurosci. 2015 Jun 3;35(22):8462-79. doi: 10.1523/JNEUROSCI.3567-14.2015.

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

Ferreira JS(1), Schmidt J(2), Rio P(1), Águas R(3), Rooyakkers A(4), Li KW(5),
Smit AB(5), Craig AM(4), Carvalho AL(6).

Author information:
(1)Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504
Coimbra, Portugal, Department of Life Sciences, University of Coimbra, 3004-517
Coimbra, Portugal.
(2)Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504
Coimbra, Portugal, Doctoral Program in Experimental Biology and Biomedicine,
Center for Neuroscience and Cell Biology and Institute for Interdisciplinary
Research, University of Coimbra, 3004-504 Coimbra, Portugal.
(3)Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504
Coimbra, Portugal.
(4)Brain Research Centre and Department of Psychiatry, University of British
Columbia, Vancouver V6T 2B5, Canada, and.
(5)Center for Neurogenomics and Cognitive Research, Neuroscience Campus
Amsterdam, VU University, Delaware Boelelaan 1085, 1081 HV, Amsterdam, The
Netherlands.
(6)Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504
Coimbra, Portugal, Department of Life Sciences, University of Coimbra, 3004-517
Coimbra, Portugal, *protected email*.

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(-/-) 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(-/-) 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.

Copyright © 2015 the authors 0270-6474/15/358462-18$15.00/0.

DOI: 10.1523/JNEUROSCI.3567-14.2015
PMID: 26041915 [Indexed for MEDLINE]


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