The Stability of NR2B in the Nucleus Accumbens Controls Behavioral and Synaptic Adaptations to Chronic Stress

Jiang, Bo; Wang, Wei; Wang, Fang; Hu, Zhuang-Li; Xiao, Jun-Li; Yang, Shuxu; Zhang, Jing; Peng, Xiaozhong; Wang, Jinhui; Chen, Jianguo

doi:10.1016/j.biopsych.2012.10.031

Cited by 42 publications

(38 citation statements)

References 61 publications

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“…46 Consistent with this hypothesis, we found that ketamine potentiates LTD in the NAc (unpublished observations). Moreover, in chronic stress models of depression, LTD in the NAc is disrupted in susceptible mice 64 and induction of LTD in the afferents to the NAc from the ventral hippocampus has a proresilient effect. 65 Taken together, the aforementioned results and our findings support the possibility that ketamine prevents potentiation of glutamatergic synapses in conditions of intense activation of glutamatergic inputs and oppose a loss of synaptic depression induced by, for example, chronic stress.…”

Section: Discussionmentioning

confidence: 99%

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

et al. 2017

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Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive. We found that one day after the injection of a low dose of ketamine, long-term potentiation (LTP) in the nucleus accumbens (NAc) was impaired. Loss of LTP was maintained for 7 days and was not associated with an altered basal synaptic transmission mediated by AMPARs and N-methyl-D-aspartate receptors (NMDARs). Inhibition of mammalian target of rapamycin signaling with rapamycin did not prevent the ketamine-induced loss of LTP but inhibited LTP in saline-treated mice. However, ketamine blunted the increase in the phosphorylation of the GluA1 subunit of AMPARs at a calcium/calmodulin-dependent protein kinase II/protein kinase C site induced by an LTP induction protocol. Moreover, ketamine caused a persistent increased phosphorylation of GluA1 at a protein kinase A site. (2R,6R)-HNK also impaired LTP in the NAc. In dopaminergic neurons of the ventral tegmental area from ketamine-or (2R,6R)-HNK-treated mice, AMPAR-mediated responses were depressed, while those mediated by NMDARs were unaltered, which resulted in a reduced AMPA/NMDA ratio, a measure of long-term synaptic depression. These results demonstrate that a single injection of ketamine or (2R,6R)-HNK induces enduring alterations in the function of AMPARs and synaptic plasticity in brain regions involved in reward-related behaviors.

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Section: Discussionmentioning

confidence: 99%

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

et al. 2017

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“…It is thus interesting to speculate that long-term SSRI treatment might decrease CaMKIIa expression as a compensatory mechanism to prevent over-strengthening of synaptic connections in several brain regions. Chronic stress induces NMDARdependent synaptic plasticity in the NAc (Belujon and Grace, 2011;Jiang et al, 2013) as well as plasticity of NAc synaptic structures (Christoffel et al, 2011), and both of these processes have been shown to involve CaMKII in various contexts (Colbran and Brown, 2004;Huang and Hsu, 2012;Robison et al, 2013). However, as CaMKIIa is present throughout the cell and is known to regulate histone modification machinery itself (Linseman et al, 2003), speculation for a specifically synaptic role for the fluoxetine-mediated reduction in CaMKIIa expression is premature.…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

Robison

Vialou

Sun

et al. 2013

Neuropsychopharmacol

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Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor DFosB and protein kinase calmodulin-dependent protein kinase II (CaMKII) are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that DFosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, wherein it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation assays, we found that DFosB binds the CaMKIIa gene promoter in NAc and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of DFosB to the CaMKIIa promoter and reduces CaMKII expression in NAc, despite the fact that DFosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIa promoter, which blocks the DFosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine-9 dimethylation of histone H3 at the CaMKIIa promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, whereas inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIa expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.

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“…Chicken anti-BDNF neutralizing antibody and chicken IgY control Ig were purchased from Promega (Madison, USA). The dosages of WY14643, fluoxetine, anti-BDNF neutralizing antibody, K252a, and PCPA were chosen based on previous reports (Collino et al 2006;Zhu et al 2010;Jiang et al 2012;Jiang et al 2013). WY14643, fluoxetine, K252a, and PCPA were administered intraperitoneally (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…Social defeat stress was performed daily for 10 days according to published protocol Jiang et al 2013). The day after the last defeat stress (day 11), all the defeated mice were housed individually and received daily injections of vehicle or tested drugs for 14 days.…”

Section: Csds Social Interaction and Sucrose Preference Experimentsmentioning

confidence: 99%

“…The day after the last defeat stress (day 11), all the defeated mice were housed individually and received daily injections of vehicle or tested drugs for 14 days. The day after the last injection (day 25), the social interaction test was performed to assay avoidance behaviors Jiang et al 2013). Social interaction test comprises two trials for 5-min each.…”

Section: Csds Social Interaction and Sucrose Preference Experimentsmentioning

confidence: 99%

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WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway

et al. 2014

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The Stability of NR2B in the Nucleus Accumbens Controls Behavioral and Synaptic Adaptations to Chronic Stress

Cited by 42 publications

References 61 publications

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway

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