Decreased expression of synapse-related genes and loss of synapses in major depressive disorder

Kang, Hyo Jung; Voleti, Bhavya; Hajszán, Tibor; Rajkowska, Grażyna; Stockmeier, Craig A.; Licznerski, Pawel; Lepack, Ashley E.; Majik, Mahesh S.; Jeong, Lak Shin; Banasr, Mounira; Son, Hyeon; Duman, Ronald S.

doi:10.1038/nm.2886

Cited by 678 publications

(531 citation statements)

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“…These changes are followed by increases in synaptic spine density/diameter, increases in both presynaptic (synapsin 1) and postsynaptic (PSD95 and GluR1) markers, and increased excitatory postsynaptic current (EPSC) frequency and amplitude (Li et al, 2010(Li et al, , 2011. These findings mesh with recent clinical data showing that in MDD there is impaired mTOR signaling (Jernigan et al, 2011) and decreased expression of synapse-related genes with a loss of synaptic spines (Kang et al, 2012). However, acute dissociative side effects and eventual fading of antidepressant responses limit widespread clinical use of ketamine.…”

Section: Introductionsupporting

confidence: 75%

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Liu

Fuchikami

Dwyer

et al. 2013

Neuropsychopharmacol

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227

162

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A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant-like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a preferential GSK-3b inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3b, increased synaptic spine density/ diameter, increased excitatory postsynaptic currents in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored.

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Section: Introductionsupporting

confidence: 75%

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Liu

Fuchikami

Dwyer

et al. 2013

Neuropsychopharmacol

Self Cite

227

162

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“…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). Indeed, a similar loss of spine synapses is observed in MDD patients (18). The possibility that loss of synapses in depression results from aberrant activity of translational pathways is supported by a report that levels of mTOR and S6K1 are decreased in postmortem PFC of depressed subjects (19).…”

Section: Discussionmentioning

confidence: 90%

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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“…Only tissue from the left hemisphere (grey matter only) was used. These cortical regions are consistently implicated in depression [17][18][19][20] and are involved in higher order functioning such as decision-making, that is impaired in suicide 21 .…”

Section: Brain Samples Clinical Characterization and Group Compositionmentioning

confidence: 99%

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

et al. 2014

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Astrocytes are glial cells specific the central nervous system involved in numerous brain functions including regulation of synaptic transmission and of immune reactions. There is mounting evidence suggesting astrocytic dysfunction in psychopathologies such as major depression, however, little is known about the underlying etiological mechanisms. Here we report a two-stage study investigating genome-wide DNA methylation associated with astrocytic markers in depressive psychopathology. We first characterized prefrontal cortex samples from 121 individuals (76 who died during a depressive episode and 45 healthy controls) for the astrocytic markers GFAP, ALDH1L1, SOX9, GLUL, SCL1A3, GJA1, and GJB6. A subset of 22 cases with consistently downregulated astrocytic markers was then compared to 17 matched controls using MBD2-sequencing followed by validation with high resolution melting and bisulfite Sanger sequencing. With these data, we generated a genome-wide methylation map unique to altered astrocyte-associated depressive psychopathology. The map revealed differentially methylated regions (DMRs) between cases and controls, the majority of which displayed reduced methylation levels in cases. Among intragenic DMRs, GRIK2 and BEGAIN were the most significant, and also significantly correlated with genes expression. Cell sorted fractions were investigated and demonstrated an important non-neuronal contribution of methylation status in BEGAIN.Functional cell assays revealed promoter and enhancer-like properties in this region, which were markedly decreased by methylation. Furthermore, a large number of our DMRs overlapped known ENCODE identified regulatory elements. Taken together, our data indicate significant differences in the methylation patterns specific to astrocytic dysfunction associated with depressive psychopathology, providing a potential framework for better understanding this disease phenotype.

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Decreased expression of synapse-related genes and loss of synapses in major depressive disorder

Cited by 678 publications

References 45 publications

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

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

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

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