REDD1 is essential for stress-induced synaptic loss and depressive behavior

Ota, Kristie T.; Liu, Rong-Jian; Voleti, Bhavya; Maldonado-Avilés, Jaime G.; Đurić, Vanja; Iwata, Masaaki; Dutheil, Sophie; Duman, Catharine H.; Boikess, Steve; Lewis, David A.; Stockmeier, Craig A.; DiLeone, Ralph J.; Rex, Christopher S.; Aghajanian, George K.; Duman, Ronald S.

doi:10.1038/nm.3513

Cited by 235 publications

(228 citation statements)

References 31 publications

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“…Recent evidence has further implicated the mTORC1/S6K1 pathway in mediating depressive behavior, demonstrating that CUS decreases activity of mTOR and downstream substrates S6K1 and S6 ribosomal protein (10,11). Decreased expression and function of the mTORC1/S6K1 pathway could contribute to dendritic reorganization and loss of spine synapses in the mPFC, as well as the hippocampus, leading to impairments in synaptic connectivity (12)(13)(14)(15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior

Dwyer

Maldonado-Avilés

Lepack

et al. 2015

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

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Current treatments for major depressive disorder (MDD) have a time lag and are ineffective for a large number of patients. Development of novel pharmacological therapies requires a comprehensive understanding of the molecular events that contribute to MDD pathophysiology. Recent evidence points toward aberrant activity of synaptic proteins as a critical contributing factor. In the present studies, we used viral-mediated gene transfer to target a key mediator of activity-dependent synaptic protein synthesis downstream of mechanistic target of rapamycin complex 1 (mTORC1) known as p70 S6 kinase 1 (S6K1). Targeted delivery of two mutants of S6K1, constitutively active or dominant-negative, to the medial prefrontal cortex (mPFC) of rats allowed control of the mTORC1/S6K1 translational pathway. Our results demonstrate that increased expression of S6K1 in the mPFC produces antidepressant effects in the forced swim test without altering locomotor activity. Moreover, expression of active S6K1 in the mPFC blocked the anhedonia caused by chronic stress, resulting in a state of stress resilience. This antidepressant response was associated with increased neuronal complexity caused by enhanced S6K1 activity. Conversely, expression of dominant-negative S6K1 in the mPFC resulted in prodepressive behavior in the forced swim test and was sufficient to cause anhedonia in the absence of chronic stress exposure. Together, these data demonstrate a critical role for S6K1 activity in depressive behaviors, and suggest that pathways downstream of mTORC1 may underlie the pathophysiology and treatment of MDD.M ajor depressive disorder (MDD) affects nearly one-fifth of the US population (1) and represents the second-leading cause of disability worldwide. Despite its prevalence, successful treatment of MDD is hindered by a lack of understanding of the molecular mechanisms underlying the disorder. Recent evidence points to a critical role for the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, which controls synaptic protein synthesis in mediating antidepressant behavior.Drugs that demonstrate rapid antidepressant activity in preclinical models of depression, such as the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, the NR2B-selective antagonist Ro 25-6981, the muscarinic antagonist scopolamine, and the metabotropic glutamate receptor 2/3 (mGluR2/3) antagonist LY341495, all share a common signaling profile through cellular protein synthesis cascades. All of these drugs increase activity of mTORC1 and its downstream substrates p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) (2-4). Pharmacological inhibition of mTORC1 in the medial prefrontal cortex (mPFC) of rats completely blocks the behavioral effects of these drugs (2-4). These data suggest that enhanced signaling through the mTORC1 pathway is required for rapid antidepressant responses. It remains unknown, however, whether direct modulation of this translational pathway is sufficient to control depressive behavior, a...

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Section: Discussionmentioning

confidence: 99%

Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior

Dwyer

Maldonado-Avilés

Lepack

et al. 2015

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

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“…This plasmid allows ubiquitous DsRed expression and conditional EGFP expression driven by floxed CMV cassette that prevents shRNA expression with U6 promoter disruption (Supplemental Figure 1A). This construct and scrambled control were packaged into AAV2 M1shRNA , as previously described (19). Neuro-(N)2a cells obtained from ATCC were used to test the efficacy of pM1shRNA.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine (ACh) receptor (mAChR) antagonist, and ketamine, an NMDA receptor antagonist, produce rapid antidepressant actions (within hours) and are effective even in treatment-resistant MDD patients (6)(7)(8). The rapid antidepressant actions of scopolamine and ketamine are dependent on glutamate release and induction of new spine synapses in the medial prefrontal cortex (mPFC) (9)(10)(11), effects that directly target the synaptic pathophysiology of MDD and chronic stress (12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Wohleb¹,

Wu²,

Gerhard³

et al. 2016

Journal of Clinical Investigation

129

112

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R e s e a R c h a R t i c l e2 4 8 2 jci.org Volume 126 Number 7 July 2016 IntroductionMajor depressive disorder (MDD) is a recurring neuropsychiatric illness that affects up to 17% of the population and causes substantial social and economic burdens (1-4). While some patients respond to existing medications, currently available antidepressants take weeks to months to have an effect, and many patients are considered treatment resistant because they fail to respond to 2 or more antidepressants (5). Recent studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine (ACh) receptor (mAChR) antagonist, and ketamine, an NMDA receptor antagonist, produce rapid antidepressant actions (within hours) and are effective even in treatment-resistant MDD patients (6-8). The rapid antidepressant actions of scopolamine and ketamine are dependent on glutamate release and induction of new spine synapses in the medial prefrontal cortex (mPFC) (9-11), effects that directly target the synaptic pathophysiology of MDD and chronic stress (12-19). However, a major question in the field is, what are the initial cellular targets that mediate the increase in glutamate transmission, leading to increased synapse formation and rapid antidepressant behavior (10, 20, 21)? One hypothesis is that scopolamine blocks muscarinic receptors on GABAergic interneurons, resulting in disinhibition of pyramidal neurons and increased glutamate transmission. Alternatively, scopolamine may act directly on pyramidal neurons to enhance synaptic plasticity and produce antidepressant behavioral responses. Recent studies suggest that the M1-type muscarinic ACh receptor (M1-AChR) subtype may mediate the antidepressant actions of scopolamine (9, 22, 23).M1-AChRs are expressed on both GABAergic interneurons and glutamatergic pyramidal neurons in the mPFC and regulate the activity of both cell types (24)(25)(26).In the present study, we used transgenic mice and viralmediated gene transfer to drive Cre-dependent expression of M1-AChR shRNA in different subtypes of GABA interneurons or glutamate neurons in the mPFC. The results demonstrate that M1-AChR knockdown in GABA interneurons, but not pyramidal neurons, blocks the antidepressant-like response to scopolamine in mouse behavioral models. In addition, we show that knockdown of M1-AChR in somatostatin (SST), but not parvalbumin (PV), interneurons, blocks the actions of scopolamine. These findings reveal that M1-AChRs on SST interneurons in the mPFC are a critical cellular target underlying the rapid antidepressant effects of scopolamine. Results CaMKII+ and GAD + cell type-specific knockdown of M1-AChR in the mPFC. To determine whether glutamatergic pyramidal neurons and GABAergic interneurons in the mPFC express M1-AChR, double immunohistology was conducted with an M1-AChR antibody and Ca 2+ /calmodulin-dependent kinase II (CaMKII; pyramidal cell) or glutamate decarboxylase-67 (GAD67; GABA interneuron) (25). The results show that CaMKII + pyramidal neurons display punctate M1-AChR labeling in the mPF...

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“…18 (Duman and Aghajanian, 2012;Ota et al, 2014;Sheline et al, 2003;Sheline et al, 1996). Compared with normal controls, depressed patients showed decreased cortical thickness, neuronal size, and neuronal and glial densities in the prefrontal cortical regions (Rajkowska et al, 1999), but the molecular mechanisms underlying these morphological alterations have not yet been identified.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%