Positive AMPA Receptor Modulation Rapidly Stimulates BDNF Release and Increases Dendritic mRNA Translation

Jourdi, Hussam; Hsu, Yu-Tien; Zhou, Miou; Qin, Qingyu; Bi, Xiaoning; Baudry, Michel

doi:10.1523/jneurosci.6078-08.2009

Cited by 204 publications

(161 citation statements)

References 53 publications

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“…AMPA receptor potentiating drugs increase the size of EPSPs, enhance LTP, enhance learning and memory, and increase BDNF [59,60]. One AMPA receptor potentiating drug, CX614, is reported to stimulate mTOR signalling and dendritic protein synthesis in cultured neurons in a BDNF-dependent manner [36]. These findings are consistent with the possibility that AMPA receptor potentiating drugs could produce rapid ketamine-like effects.…”

Section: Potential Synaptogenic Targetssupporting

confidence: 52%

“…The lack of evidence for antidepressant reversal could reflect the technical challenges and time commitment required to conduct these difficult studies. In addition, it is possible that although BDNF expression is increased, typical antidepressant treatments do not increase BDNF release, which is required for increased synaptogenesis [23,35,36].…”

Section: Regulation Of Neuronal Processes and Synaptogenesis By Stressmentioning

confidence: 99%

“…This is critical as mTOR is expressed in neuronal and glial cell bodies, which could mask changes in the smaller dendritic compartment. Second, the behavioural analysis was conducted 30 min after ketamine administration, when ketamine levels are still high in brain and corresponds to the time when patients experience mild psychotomimetic and dissociative effects of ketamine [36,40]. This would also correspond to the time when ketamine increases levels of glutamate [47], which could underlie the increased activity observed in the FST.…”

Section: Role Of Mammalian Target Of Rapamycin Signalling In the Actimentioning

confidence: 99%

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A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

Duman

2012

Phil. Trans. R. Soc. B

297

190

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Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor, in limbic structures of the brain. These changes in neurotrophic factor expression and function result in structural alterations, including regulation of neurogenesis, dendrite length and spine density in hippocampus and prefrontal cortex (PFC). The deleterious effects of stress could contribute to the reduced volume of these brain regions in depressed patients. Conversely, the actions of antidepressant treatment could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies have identified a novel, rapid-acting antidepressant, ketamine, in treatment-resistant depressed patients that addresses the limitations of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and correspond to rapid behavioural actions of ketamine in models of depression. Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine.

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Section: Potential Synaptogenic Targetssupporting

confidence: 52%

Section: Regulation Of Neuronal Processes and Synaptogenesis By Stressmentioning

confidence: 99%

Section: Role Of Mammalian Target Of Rapamycin Signalling In the Actimentioning

confidence: 99%

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A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

Duman

2012

Phil. Trans. R. Soc. B

297

190

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“…The ketamine-induced HDAC5 phosphorylation is suggested to be CaMKII and PKD dependent. Preclinical studies demonstrate that ketamine enhances glutamatergic transmission and subsequent stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which leads to activation of voltage-dependent Ca 2+ channels and activity-dependent brain-derived neurotrophic factor release (27,28). This might be a mechanistic explanation for how CaMKII and PKD are activated by ketamine.…”

Section: Discussionmentioning

confidence: 99%

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Choi

Lee

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II-and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamineinduced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.ketamine | HDAC | depression | hippocampus D epression is a multifaceted illness, characterized by somatic, cognitive, and behavioral changes. All currently available antidepressants primarily act via monoaminergic neurotransmitters, such as serotonin and/or noradrenaline (1). Currently available pharmacotherapies for depression provide some relief for patients, but these agents have significant limitations (1). In this context, new antidepressants with faster onset of action and greater efficacy are needed (2).The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown remarkable consistency in rapidly ameliorating depressive symptoms in major depressive disorder (MDD) (3). Preclinical studies have demonstrated that ketamine produces rapid antidepressant responses (within hours) (4, 5). Ketamine's antidepressant effects in rodents are associated with activation of several signaling systems including the mammalian target of rapamycin complex 1 (mTORC1) (4), brain derived neurotrophic factor (BDNF) and elongation factor 2 (EF2) kinase (5). Despite these remarkable effects, the widespread use of ketamine is limited by potential side effects and abuse. Thus, studies are necessary to further elucidate mechanistic actions of ketamine at cellular and network levels.Recent studies have generated evidence that epigenetic regulation is closely involved in the pathophysiology of depression and in the therapeutic mechanisms of typical antidepressants (6, 7). In addition, reports that sodium butyrate, a histone deacetylase (HDAC) inhibitor, has antidepressant effects indicate that HDAC inhibition is sufficient to produce an antidepressant response (8). HDACs are a family of enzymes capable of repressing gene expression by removing acetyl groups from histones to produce a less accessible chromatin structure (9).Previous studies demonstrate that the...

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“…CX516 is a direct AMPA receptor positive modulator or 'ampakine' known to increase LTP and raise BDNF levels, thus potentially increasing surface expression of AMPA receptors (Jourdi et al, 2009). Conceptually, it was thought that CX516 would help compensate or correct the AMPA receptor deficit resulting from mGlu pathway overactivity.…”

Section: Agents Activating Surface Ampa Receptors and Activitymentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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Positive AMPA Receptor Modulation Rapidly Stimulates BDNF Release and Increases Dendritic mRNA Translation

Cited by 204 publications

References 53 publications

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

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