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Neuroscience Article from EJN

Neuroscience Article from EJN - European Journal of...

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SYNAPTIC MECHANISMS Nucleus accumbens neurons exhibit synaptic scaling that is occluded by repeated dopamine pre-exposure Xiu Sun and Marina E. Wolf Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA Keywords : AMPA receptors, homeostatic plasticity, rat, synaptic scaling, ubiquitin-proteasome system 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 Ca 2+ 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. Introduction Considerable evidence suggests that drug addiction involves activity- dependent plasticity at glutamate synapses within neuronal circuits important for motivated behaviors (Wolf et al. , 2004; Kauer & Malenka, 2007). Most work has focused on long-term potentiation and long-term depression. These rapidly induced forms of plasticity contribute to the initiation of addiction-related adaptations (Kauer, 2004) and may be involved in rapid responses to drug re-exposure (Thomas et al. , 2001; Brebner et al. , 2005; Boudreau et al. , 2007; Kourrich et al. , 2007; Anderson et al. , 2008; Famous et al. , 2008). However, they do not explain slowly developing plasticity during drug withdrawal, which involves prolonged changes in the activity of neuronal pathways.
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