Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Aceto, Giuseppe; Colussi, Claudia; Leone, Lucia; Fusco, Salvatore; Rinaudo, Marco; Scala, Federico; Green, Thomas A.; Laezza, Fernanda; D’Ascenzo, Marcello; Grassi, Claudio

doi:10.1073/pnas.1917423117

Cited by 34 publications

(37 citation statements)

References 87 publications

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“…Consistent with the hypothesis of beta-catenin having therapeutic effects, overactive GSK-3b is associated with depressive symptoms [98]. Also, GSK-3b mediates maladaptive NAc plasticity [99], and knockdown prevents depressive symptoms. GSK-3b is also inhibited lithium, and ketamine, which is necessary for its antidepressant effects [18].…”

Section: Set Intersectionsupporting

confidence: 64%

Identifying Potential Novel Pathways and Therapeutic Targets of Major Depressive Disorder with Functional Genomics

Bao¹

2021

Preprint

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Background: Major depressive disorder (MDD) is a debilitating illness and a leading cause of disability, but its pathophysiology remains to be completely elucidated. Resistance to traditional antidepressant treatment is highly prevalent within patient populations. Ketamine, a rapid-acting antidepressant that has shown success in treating resistant patients, is hypothesized to function by modulating excitatory and inhibitory neurotransmitters. This has led to a paradigm shift from the monoaminergic hypothesis, towards a glutamate and neuroplasticity hypothesis, though this picture may still be incomplete. The purpose of this study is to identify novel systems potentially implicated in MDD and suggest potential therapeutic mechanisms.Methods: An integrative genomics and systems biology approach was used to identify genes and pathways that may be relevant to MDD. Starting with genes implicated in current, well-established paradigms, a correlation analysis was used to query publicly available microarray datasets to identify potential genes that may be relevant to MDD. Systems and pathways of interest were identified through functional enrichment. Through a manual review, genes of systems and pathways potentially relevant to MDD were used to generate a protein interaction network. Interesting genes identified from the network were functionally enriched and clustered to identify new high-level themes. Genes from the protein interaction network were then classified into sets based on different paradigms using functional annotations. Genes belonging to multiple sets – and thus being involved in multiple different paradigms relevant to MDD – were identified for future research.Results: The highest-ranked enrichment cluster contained GABAeric signaling, retrograde endocannabinoid signaling, and morphine addiction. Other interesting pathways identified were T cell receptor signaling, cocaine addiction, and nicotine addiction. Other broad themes identified in other clusters were calcium, serotonin, the immune system, TGF beta, glutamate, telomeres, the guanine nucleotide exchange factor, the extracellular matrix, and DNA regulation. Potential genes of interest are listed in Chart 3.Conclusions: Throughout the study, interesting genes, groups of genes, and systems were identified manually and systematically, some of which validate existing literature and some give possible directions for future research. Further experiments are required to confirm causal links.

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Section: Set Intersectionsupporting

confidence: 64%

Identifying Potential Novel Pathways and Therapeutic Targets of Major Depressive Disorder with Functional Genomics

Bao¹

2021

Preprint

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“…In association with the chronic stress-induced changes in the excitability of MSNs, several studies have reported changes in dendritic spine structure and density, which involve various neurotrophic factors, cell adhesion molecules, and kinases [104][105][106][107] . However, these findings are contradictory in terms of the correlation between these structural changes in spines and depressive/resilient behavior, which thus remains to be elucidated (Table 2).…”

Section: Chronic Stress-induced Plasticity Changes In Msns In the Nacmentioning

confidence: 99%

Stress and the dopaminergic reward system

Baik

2020

Exp Mol Med

211

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Dopamine regulates reward-related behavior through the mesolimbic dopaminergic pathway. Stress affects dopamine levels and dopaminergic neuronal activity in the mesolimbic dopamine system. Changes in mesolimbic dopaminergic neurotransmission are important for coping with stress, as they allow adaption to behavioral responses to various environmental stimuli. Upon stress exposure, modulation of the dopaminergic reward system is necessary for monitoring and selecting the optimal process for coping with stressful situations. Aversive stressful events may negatively regulate the dopaminergic reward system, perturbing reward sensitivity, which is closely associated with chronic stress-induced depression. The mesolimbic dopamine system is excited not only by reward but also by aversive stressful stimuli, which adds further intriguing complexity to the relationship between stress and the reward system. This review focuses on lines of evidence related to how stress, especially chronic stress, affects the mesolimbic dopamine system, and discusses the role of the dopaminergic reward system in chronic stress-induced depression.

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“…Synaptic plasticity and cognition are affected by stress (Russo and Nestler, 2013, Dwivedi and Pandey, 2000, Aceto et al, 2020). While acute stress can improve cognitive performance, exposure to persistent stress causes cognitive impairment (Yuen et al, 2012, Bellani et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Integrated Regulation of PKA by Fast and Slow Neurotransmission in the Nucleus Accumbens Controls Plasticity and Stress Responses

Thomas

Hernández

et al. 2021

Preprint

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Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIβ. We find that glutamate-dependent reduction in Cdk5-dependent RIIβ phosphorylation alters the PKA holoenzyme auto-inhibitory state to increase PKA signaling in response to dopamine. Disruption of RIIβ phosphorylation by Cdk5, consequently, enhances cortico-ventral striatal synaptic plasticity. Acute and chronic stress in rats inversely modulates RIIβ phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIβ regulation by Cdk5 improves behavioral response to stress. This new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is likely important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.

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Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Cited by 34 publications

References 87 publications

Identifying Potential Novel Pathways and Therapeutic Targets of Major Depressive Disorder with Functional Genomics

Identifying Potential Novel Pathways and Therapeutic Targets of Major Depressive Disorder with Functional Genomics

Stress and the dopaminergic reward system

Integrated Regulation of PKA by Fast and Slow Neurotransmission in the Nucleus Accumbens Controls Plasticity and Stress Responses

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