Prefrontal cortex GABAergic deficits and circuit dysfunction in the pathophysiology and treatment of chronic stress and depression

Ghosal, Sriparna; Hare, Brendan D.; Duman, Ronald S.

doi:10.1016/j.cobeha.2016.09.012

Cited by 160 publications

(113 citation statements)

References 63 publications

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“…Notably, regarding the differential phosphorylation changes induced by ketamine, but not by CUMS, ''synapse'' still accounts for a large proportion of the categories from the GO analysis (Figures 5B,E). Consistent with our study, many previous studies have shown that ketamine can reverse the synaptic deficits caused by stress (Li et al, 2011;Belujon and Grace, 2014;Ghosal et al, 2017). Surprisingly, only a few phosphorylation sites were overlapping between the mPFC and the NAc induced by CUMS and ketamine, respectively (Supplementary Figure S5).…”

Section: Discussionsupporting

confidence: 92%

A Brain Signaling Framework for Stress-Induced Depression and Ketamine Treatment Elucidated by Phosphoproteomics

Xiao

Luo

Yang

et al. 2020

Front. Cell. Neurosci.

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Depression is a common affective disorder characterized by significant and persistent low mood. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to have a rapid and durable antidepressant effect, but the mechanisms are unclear. Protein phosphorylation is a post-translational modification that plays a crucial role in cell signaling. Thus, we present a phosphoproteomics approach to investigate the mechanisms underlying stress-induced depression and the rapid antidepressant effect of ketamine in mice. We analyzed the phosphoprotein changes induced by chronic unpredictable mild stress (CUMS) and ketamine treatment in two known mood control centers, the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). We initially obtained >8,000 phosphorylation sites. Quantitation revealed 3,988 sites from the mPFC and 3,196 sites from the NAc. Further analysis revealed that changes in synaptic transmission-related signaling are a common feature. Notably, CUMS-induced changes were reversed by ketamine treatment, as shown by the analysis of commonly altered sites. Ketamine also induced specific changes, such as alterations in synapse organization, synaptic transmission, and enzyme binding. Collectively, our findings establish a signaling framework for stress-induced depression and the rapid antidepressant effect of ketamine.

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Section: Discussionsupporting

confidence: 92%

A Brain Signaling Framework for Stress-Induced Depression and Ketamine Treatment Elucidated by Phosphoproteomics

Xiao

Luo

Yang

et al. 2020

Front. Cell. Neurosci.

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“…Moreover, it will allow the optogenetic and/or CRE-line targeting of very specific neurons for the purposes of investigation (Bernard, Sorensen, & Lein, 2009;Cardin et al, 2010) and treatment (Hunt et al, 2013;Ghosal, Hare, & Duman, 2017;Chohan & Moore, 2016). Precision is especially important in translational research, and understanding the role of particular neurons in normal and diseased functioning requires a cumulative knowledge incorporating morphology, electrophysiology, and molecular expression profiles (Seung & Sümbül, 2014;Cadwell et al, 2016;Armananzas & Ascoli, 2015;PING, 2008).…”

Section: Discussionmentioning

confidence: 99%

Molecular Expression Profiles of Morphologically Defined Hippocampal Neuron Types: Empirical Evidence and Relational Inferences

White

Rees

Wheeler

et al. 2019

Preprint

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Gene and protein expressions are key determinants of cellular function. Neurons are the building blocks of brain circuits, yet the relationship between their molecular identity and the spatial distribution of their dendritic inputs and axonal outputs remain incompletely understood. The open-source knowledge base Hippocampome.org amasses such transcriptomic data from the scientific literature for morphologically defined neuron types in the rodent hippocampal formation: dentate gyrus (DG), CA3, CA2, CA1, subiculum (SUB), and entorhinal cortex (EC).Positive, negative, or mixed expression reports were initially obtained from published articles directly connecting molecular evidence to neurons with known axonal and dendritic patterns across hippocampal layers. Here, we supplement this information by collating, formalizing, and leveraging relational expression inferences (REIs) that link a gene or protein expression or lack thereof to that of another molecule or to an anatomical location. With these additional interpretations, we freely release online a comprehensive human-and machine-readable molecular profile for the more than 100 neuron types in Hippocampome.org. Analysis of these data ascertains the ability to distinguish unequivocally most neuron types in each of the major subdivisions of the hippocampus based on currently known biochemical markers. Moreover, grouping neuron types by expression similarity reveals eight super-families characterized by a few defining molecules. Significance StatementThe molecular composition of cells underlies their structure, activity, and function. Neurons are arguably the most diverse cell types with their characteristic tree-like shapes mediating synaptic communication throughout the brain. Biochemical marker data are available online for hundreds of morphologically identified neuron types in the mammalian hippocampus, including expression of calcium-binding proteins, receptors, and enzymes. Here, we augment this evidence by systematically applying logical rules empirically derived from the published literature (e.g."presence of molecule X implies lack of molecule Y"). The resulting substantially expanded expression profiles provide nearly unique molecular identities for most known hippocampal 3 neuron types while revealing previously unrecognized genetic similarities across anatomical regions and morphological phenotypes.

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“…The evidence from clinical trials indicated that GABAergic neurotransmission and GABA content were substantially decreased in depressed patients . Additionally, GABAergic interneuron is a leading cause of alteration in depressed patients and is beneficial to the increased of self‐focus and cogitation in depressive patients . Our previous electrophysiological study showed that inhibitory synaptic transmission was down‐regulated in NAc GABAergic neurons in the depression model .…”

Section: Introductionmentioning

confidence: 91%

“…[6][7][8] Additionally, GABAergic interneuron is a leading cause of alteration in depressed patients and is beneficial to the increased of self-focus and cogitation in depressive patients. 9,10 Our previous electrophysiological study showed that inhibitory synaptic transmission was down-regulated in NAc GABAergic neurons in the depression model. 11 The lower GABA content from presynaptic terminals in the NAc tissue may be conferred to the aetiology of chronic unpredictable mild stress (CUMS)-induced depression.…”

Section: Introductionmentioning

confidence: 99%

The molecular mechanism underlying GABAergic dysfunction in nucleus accumbens of depression‐like behaviours in mice

Zhang

Wang

et al. 2019

J Cellular Molecular Medi

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Depression is the most frequent psychiatric disorder in the world. Recent evidence has shown that stress‐induced GABAergic dysfunction in the nucleus accumbens (NAc) contributed to the pathophysiology of depression. However, the molecular mechanisms underlying these pathological changes remain unclear. In this study, mice were constantly treated with the chronic unpredictable mild stress (CUMS) till showing depression‐like behaviours expression. GABA synthesis, release and uptake in the NAc tissue were assessed by analysing the expression level of genes and proteins of Gad‐1, VGAT and GAT‐3 by qRT‐PCR and Western blotting. The miRNA/mRNA network regulating GABA was constructed based on the bioinformatics prediction software and further validated by dual‐luciferase reporter assay in vitro and qRT‐PCR in vivo, respectively. Our results showed that the expression level of GAT‐3, Gad‐1 and VGAT mRNA and protein significantly decreased in the NAc tissue from CUMS‐induced depression‐like mice than that of control mice. However, miRNA‐144‐3p, miRNA‐879‐5p, miR‐15b‐5p and miRNA‐582‐5p that directly down‐regulated the expression of Gad‐1, VGAT and GAT‐3 were increased. In the mRNA/miRNA regulatory GABA network, Gad‐1 and VGAT were directly regulated by binding seed sequence of miR‐144‐3p, and miR‐15b‐5p, miR‐879‐5p could be served negative post‐regulators by binding to the different sites of VGAT 3′‐UTR. Chronic stress causes the impaired GABA synthesis, release and uptake by up‐regulating miRNAs and down‐regulating mRNAs and proteins, which may reveal the molecular mechanisms for the decreased GABA concentrations in the NAc tissue of CUMS‐induced depression.

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Prefrontal cortex GABAergic deficits and circuit dysfunction in the pathophysiology and treatment of chronic stress and depression

Cited by 160 publications

References 63 publications

A Brain Signaling Framework for Stress-Induced Depression and Ketamine Treatment Elucidated by Phosphoproteomics

A Brain Signaling Framework for Stress-Induced Depression and Ketamine Treatment Elucidated by Phosphoproteomics

Molecular Expression Profiles of Morphologically Defined Hippocampal Neuron Types: Empirical Evidence and Relational Inferences

The molecular mechanism underlying GABAergic dysfunction in nucleus accumbens of depression‐like behaviours in mice

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