Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure

Xiu Sun, Marina Wolf

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Synaptic scaling has been proposed as a form of plasticity that may contribute to drug addiction but it has not been previously demonstrated in the nucleus accumbens (NAc), a critical region for addiction. Here we demonstrate bidirectional synaptic scaling in postnatal rat NAc neurons that were co-cultured with prefrontal cortical neurons to restore excitatory input. Prolonged activity blockade (1-3 days) with an AMPA receptor antagonist increased cell surface (synaptic and extrasynaptic) glutamate receptor 1 (GluR1) and GluR2 but not GluR3, as well as GluR1/2 co-localization on the cell surface and total GluR1 and GluR2 protein levels. A prolonged increase in activity (bicuculline, 48 h) produced opposite effects. These results suggest that GluR1/2-containing AMPA receptors undergo synaptic scaling in NAc neurons. GluR1 and GluR2 surface expression was also increased by tetrodotoxin alone or in combination with an N-methyl-d-aspartate receptor or AMPA receptor antagonist but not by the l-type Ca2+ channel antagonist nifedipine. A cobalt-quenching assay confirmed the immunocytochemical results indicating that synaptic scaling after activity blockade did not involve a change in abundance of GluR2-lacking AMPA receptors. Increased AMPA receptor surface expression after activity blockade required protein synthesis and was occluded by inhibition of the ubiquitin-proteasome system. Repeated dopamine (DA) treatment, which leads to upregulation of surface GluR1 and GluR2, occluded activity blockade-induced synaptic scaling. These latter results indicate an interaction between cellular mechanisms involved in synaptic scaling and adaptive mechanisms triggered by repeated DA receptor stimulation, suggesting that synaptic scaling may not function normally after exposure to DA-releasing drugs such as cocaine.

Original languageEnglish (US)
Pages (from-to)539-550
Number of pages12
JournalEuropean Journal of Neuroscience
Volume30
Issue number4
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

Fingerprint

Nucleus Accumbens
Glutamate Receptors
AMPA Receptors
Dopamine
Neurons
Dopamine Agents
Bicuculline
Tetrodotoxin
Dopamine Receptors
Proteasome Endopeptidase Complex
Nifedipine
Ubiquitin
Cobalt
Cocaine
Substance-Related Disorders
Proteins
Up-Regulation

Keywords

  • AMPA receptors
  • Homeostatic plasticity
  • Rat
  • Synaptic scaling
  • Ubiquitin-proteasome system

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure. / Sun, Xiu; Wolf, Marina.

In: European Journal of Neuroscience, Vol. 30, No. 4, 01.08.2009, p. 539-550.

Research output: Contribution to journalArticle

@article{c58177ab81814df29eef3aae15944dd4,
title = "Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure",
abstract = "Synaptic scaling has been proposed as a form of plasticity that may contribute to drug addiction but it has not been previously demonstrated in the nucleus accumbens (NAc), a critical region for addiction. Here we demonstrate bidirectional synaptic scaling in postnatal rat NAc neurons that were co-cultured with prefrontal cortical neurons to restore excitatory input. Prolonged activity blockade (1-3 days) with an AMPA receptor antagonist increased cell surface (synaptic and extrasynaptic) glutamate receptor 1 (GluR1) and GluR2 but not GluR3, as well as GluR1/2 co-localization on the cell surface and total GluR1 and GluR2 protein levels. A prolonged increase in activity (bicuculline, 48 h) produced opposite effects. These results suggest that GluR1/2-containing AMPA receptors undergo synaptic scaling in NAc neurons. GluR1 and GluR2 surface expression was also increased by tetrodotoxin alone or in combination with an N-methyl-d-aspartate receptor or AMPA receptor antagonist but not by the l-type Ca2+ channel antagonist nifedipine. A cobalt-quenching assay confirmed the immunocytochemical results indicating that synaptic scaling after activity blockade did not involve a change in abundance of GluR2-lacking AMPA receptors. Increased AMPA receptor surface expression after activity blockade required protein synthesis and was occluded by inhibition of the ubiquitin-proteasome system. Repeated dopamine (DA) treatment, which leads to upregulation of surface GluR1 and GluR2, occluded activity blockade-induced synaptic scaling. These latter results indicate an interaction between cellular mechanisms involved in synaptic scaling and adaptive mechanisms triggered by repeated DA receptor stimulation, suggesting that synaptic scaling may not function normally after exposure to DA-releasing drugs such as cocaine.",
keywords = "AMPA receptors, Homeostatic plasticity, Rat, Synaptic scaling, Ubiquitin-proteasome system",
author = "Xiu Sun and Marina Wolf",
year = "2009",
month = "8",
day = "1",
doi = "10.1111/j.1460-9568.2009.06852.x",
language = "English (US)",
volume = "30",
pages = "539--550",
journal = "European Journal of Neuroscience",
issn = "0953-816X",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure

AU - Sun, Xiu

AU - Wolf, Marina

PY - 2009/8/1

Y1 - 2009/8/1

N2 - Synaptic scaling has been proposed as a form of plasticity that may contribute to drug addiction but it has not been previously demonstrated in the nucleus accumbens (NAc), a critical region for addiction. Here we demonstrate bidirectional synaptic scaling in postnatal rat NAc neurons that were co-cultured with prefrontal cortical neurons to restore excitatory input. Prolonged activity blockade (1-3 days) with an AMPA receptor antagonist increased cell surface (synaptic and extrasynaptic) glutamate receptor 1 (GluR1) and GluR2 but not GluR3, as well as GluR1/2 co-localization on the cell surface and total GluR1 and GluR2 protein levels. A prolonged increase in activity (bicuculline, 48 h) produced opposite effects. These results suggest that GluR1/2-containing AMPA receptors undergo synaptic scaling in NAc neurons. GluR1 and GluR2 surface expression was also increased by tetrodotoxin alone or in combination with an N-methyl-d-aspartate receptor or AMPA receptor antagonist but not by the l-type Ca2+ channel antagonist nifedipine. A cobalt-quenching assay confirmed the immunocytochemical results indicating that synaptic scaling after activity blockade did not involve a change in abundance of GluR2-lacking AMPA receptors. Increased AMPA receptor surface expression after activity blockade required protein synthesis and was occluded by inhibition of the ubiquitin-proteasome system. Repeated dopamine (DA) treatment, which leads to upregulation of surface GluR1 and GluR2, occluded activity blockade-induced synaptic scaling. These latter results indicate an interaction between cellular mechanisms involved in synaptic scaling and adaptive mechanisms triggered by repeated DA receptor stimulation, suggesting that synaptic scaling may not function normally after exposure to DA-releasing drugs such as cocaine.

AB - Synaptic scaling has been proposed as a form of plasticity that may contribute to drug addiction but it has not been previously demonstrated in the nucleus accumbens (NAc), a critical region for addiction. Here we demonstrate bidirectional synaptic scaling in postnatal rat NAc neurons that were co-cultured with prefrontal cortical neurons to restore excitatory input. Prolonged activity blockade (1-3 days) with an AMPA receptor antagonist increased cell surface (synaptic and extrasynaptic) glutamate receptor 1 (GluR1) and GluR2 but not GluR3, as well as GluR1/2 co-localization on the cell surface and total GluR1 and GluR2 protein levels. A prolonged increase in activity (bicuculline, 48 h) produced opposite effects. These results suggest that GluR1/2-containing AMPA receptors undergo synaptic scaling in NAc neurons. GluR1 and GluR2 surface expression was also increased by tetrodotoxin alone or in combination with an N-methyl-d-aspartate receptor or AMPA receptor antagonist but not by the l-type Ca2+ channel antagonist nifedipine. A cobalt-quenching assay confirmed the immunocytochemical results indicating that synaptic scaling after activity blockade did not involve a change in abundance of GluR2-lacking AMPA receptors. Increased AMPA receptor surface expression after activity blockade required protein synthesis and was occluded by inhibition of the ubiquitin-proteasome system. Repeated dopamine (DA) treatment, which leads to upregulation of surface GluR1 and GluR2, occluded activity blockade-induced synaptic scaling. These latter results indicate an interaction between cellular mechanisms involved in synaptic scaling and adaptive mechanisms triggered by repeated DA receptor stimulation, suggesting that synaptic scaling may not function normally after exposure to DA-releasing drugs such as cocaine.

KW - AMPA receptors

KW - Homeostatic plasticity

KW - Rat

KW - Synaptic scaling

KW - Ubiquitin-proteasome system

UR - http://www.scopus.com/inward/record.url?scp=69249130456&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69249130456&partnerID=8YFLogxK

U2 - 10.1111/j.1460-9568.2009.06852.x

DO - 10.1111/j.1460-9568.2009.06852.x

M3 - Article

C2 - 19674091

AN - SCOPUS:69249130456

VL - 30

SP - 539

EP - 550

JO - European Journal of Neuroscience

JF - European Journal of Neuroscience

SN - 0953-816X

IS - 4

ER -