Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell

Crofton, Elizabeth J.; Nenov, Miroslav N.; Zhang, Yafang; Scala, Federico; Page, Sean A.; McCue, David; Li, Dingge; Hommel, Jonathan D.; Laezza, Fernanda; Green, Thomas A.

doi:10.1016/j.neuropharm.2017.01.020

Cited by 52 publications

(56 citation statements)

References 78 publications

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“…Additionally, a similar pro-depression-like effect can be induced by GSK3β overexpression in the nucleus accumbens, while the expression of inactive GSK3β mutant promotes resilience to social defeat stress [46]. On the other hand, Crofton et al, found that the knockdown of GSK3β in the nucleus accumbens shell increases cocaine self-administration and depression-like behavior in social contact tests in rats [47,48]. This discrepancy between stressor type and its effect within the same structure is also reflected in the activity of the ventral tegmental area, a midbrain structure that delivers input to nucleus accumbens.…”

Section: Gsk3β Expression Profile and Activity In Depressionmentioning

confidence: 99%

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Duda

Hajka

Wójcicka

et al. 2020

Cells

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Glycogen synthase kinase 3β (GSK3β), originally described as a negative regulator of glycogen synthesis, is a molecular hub linking numerous signaling pathways in a cell. Specific GSK3β inhibitors have anti-depressant effects and reduce depressive-like behavior in animal models of depression. Therefore, GSK3β is suggested to be engaged in the pathogenesis of major depressive disorder, and to be a target and/or modifier of anti-depressants' action. In this review, we discuss abnormalities in the activity of GSK3β and its upstream regulators in different brain regions during depressive episodes. Additionally, putative role(s) of GSK3β in the pathogenesis of depression and the influence of anti-depressants on GSK3β activity are discussed.Cells 2020, 9, 727 2 of 26 any of the groups listed above. Additionally, electroconvulsive therapy, conducted for the first time in 1938, is still widely used in the treatment of MDD, especially in its drug-refractory form [5].Although the monoaminergic hypothesis has led to the invention of many successful therapeutic strategies based on the elevation of levels of NA and 5-HT in the synaptic cleft, it does not explain the anti-depressant effect of lithium and the rapid action of ketamine in the treatment of mood disorders [6]. Therefore, factors other than neurotransmission must be taken into consideration in the context of the MDD pathogenesis. One of them is glycogen synthase kinase 3β (GSK3β) signaling. Glycogen Synthase Kinase 3βGSK3 was isolated in 1980, from rabbit skeletal muscle, and described as a highly specific serine/threonine kinase for glycogen synthase [7]. There are two isozymes of GSK3, α and β, and both are expressed at similar levels in the mouse brain [8]. In the human brain, the β isozyme predominates [9]. Therefore, GSK3β is expected to be crucial for the human central nervous system functioning. The activity of GSK3β is regulated positively and negatively by phosphorylation on Tyr216 and Ser9, respectively [10,11]. Whereas phosphorylation of the residue Tyr216 occurs during the GSK3β translation process and results in a synthesis of the fully activated kinase, Ser9 phosphorylation seems to be the main regulatory modification during the enzyme lifespan [12]. Ser9-phosphorylated GSK3β remains inhibited, and dephosphorylation of the residue results in the disinhibition (activation) of the kinase.GSK3β is part of numerous cellular signaling pathways, and its activity can be regulated, directly or indirectly, by several kinases, phosphatases, and proteases. The wide spectrum of GSK3β substrates, including transcription factors, glycolytic enzymes, pro-and anti-apoptotic factors, mitochondrial channels, membrane receptors, and cytoskeleton-associated proteins, makes GSK3β a central point of the cell homeostasis maintenance [13]. The activity of GSK3β affects energy metabolism, cell survival, proliferation, apoptosis, membrane polarity, internalization of the synaptic receptors, neuroplasticity, neurotransmission, amyloid processing, and many other processes [13].Ex...

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Section: Gsk3β Expression Profile and Activity In Depressionmentioning

confidence: 99%

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Duda

Hajka

Wójcicka

et al. 2020

Cells

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“…Recently, a role for the nucleus accumbens (NAc), the main anatomical constituent of the ventral striatum (VS), is emerging in the context of anxiety (Gunaydin and Kreitzer, 2016;Levita et al, 2012) interconnected with the NAc function in behavioral adaptation (Haber and Behrens, 2014). In rodents, anxiety-like behaviors can be regulated by pharmacological (Heshmati et al, 2016;Lopes et al, 2012) or genetic (Crofton et al, 2017;Feng et al, 2017;Shen et al, 2016;Zhao and Gammie, 2018) manipulation of NAc neurochemistry. Importantly, anxiety-like behaviors have also been related to variations in NAc mitochondrial function Van Der Kooij et al, 2018) and brain energy metabolism (Larrieu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Nucleus accumbens neurochemistry in human anxiety: A 7 T¹H-MRS study

Strasser

Xin

Gruetter

et al. 2018

Preprint

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Individual differences in anxiety provide a differential predisposition to develop neuropsychiatric disorders. The neurochemical underpinnings of anxiety remain elusive, particularly in deep structures, such as the nucleus accumbens (NAc) whose involvement in anxiety is being increasingly recognized.We examined the associations between the neurochemical profile of human NAc metabolites involved in neural excitation and inhibition and inter-individual variation in temperamental and situational anxiety. Twenty-seven healthy 20-30 years-old human males were phenotyped with questionnaires for state and trait anxiety (State-Trait Anxiety Inventory, STAI), social anxiety (Liebowitz Social Anxiety Scale), depression (Beck Depression Inventory, BDI) and fatigue (Mental and Physical State Energy and Fatigue Scales, SEF). Using proton magnetic resonance spectroscopy ( 1 H-MRS) at 7 Tesla (7T), we measured metabolite levels for glutamate, glutamine, GABA and taurine in the NAc with. Salivary cortisol was also measured. Strikingly, trait anxiety was negatively associated with NAc taurine content. Perceived situational stress was negatively associated with NAc GABA, while positively with the Glu/GABA ratio. These findings were specific, as no correlation was observed between NAc taurine or GABA and other phenotypic variables examined (i.e., state anxiety, social anxiety, depression, or cortisol), except for a negative correlation between taurine and state physical fatigue. This first 7T study of NAc neurochemistry shows relevant metabolite associations with individual variation in anxiety traits and situational stress and state anxiety measurements. The novel identified association between NAc taurine levels and trait anxiety may pave the way for clinical studies aimed at identifying new treatments for anxiety and related disorders.

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“…Analysis of the swim trajectories revealed significant Drug × Trial Day interactions when Center Time [ F (6,60) = 2.3, p = 0.038] and Center Distance [ F (6,60) = 2.2, p = 0.04] were analyzed. By Trial Day 4, SB 216763 treatment resulted in the rats spending significantly more time in the center of the pool (SB vs. Veh, p = 0.023, Bonferroni post hoc , Figures 1D,E ) which may reflect an anxiolytic effect of the drug ( Crofton et al, 2017 ).…”

Section: Resultsmentioning

confidence: 98%

Disparate Effects of Lithium and a GSK-3 Inhibitor on Neuronal Oscillatory Activity in Prefrontal Cortex and Hippocampus

Nguyen

Fan

George

et al. 2018

Front. Aging Neurosci.

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Glycogen synthase kinase-3 (GSK-3) plays a critical role in cognitive dysfunction associated with Alzheimer’s disease (AD), yet the mechanism by which GSK-3 alters cognitive processes in other disorders, such as schizophrenia, remains unknown. In the present study, we demonstrated a role for GSK-3 in the direct regulation of neuronal oscillations in hippocampus (HIP) and prelimbic cortex (PL). A comparison of the GSK-3 inhibitors SB 216763 and lithium demonstrated disparate effects of the drugs on spatial memory and neural oscillatory activity in HIP and PL. SB 216763 administration improved spatial memory whereas lithium treatment had no effect. Analysis of neuronal local field potentials in anesthetized animals revealed that whereas both repeated SB 216763 (2.5 mg/kg) and lithium (100 mg/kg) induced a theta frequency spike in HIP at approximately 10 Hz, only SB 216763 treatment induced an overall increase in theta power (4–12 Hz) compared to vehicle. Acute administration of either drug suppressed slow (32–59 Hz) and fast (61–100 Hz) gamma power. In PL, both drugs induced an increase in theta power. Repeated SB 216763 increased HIP–PL coherence across all frequencies except delta, whereas lithium selectively suppressed delta coherence. These findings demonstrate that GSK-3 plays a direct role in the regulation of theta oscillations in regions critically involved in cognition, and highlight a potential mechanism by which GSK-3 may contribute to cognitive decline in disorders of cognitive dysfunction.

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Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell

Cited by 52 publications

References 78 publications

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Nucleus accumbens neurochemistry in human anxiety: A 7 T¹H-MRS study

Disparate Effects of Lithium and a GSK-3 Inhibitor on Neuronal Oscillatory Activity in Prefrontal Cortex and Hippocampus

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Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell

Cited by 52 publications

References 78 publications

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Nucleus accumbens neurochemistry in human anxiety: A 7 T1H-MRS study

Disparate Effects of Lithium and a GSK-3 Inhibitor on Neuronal Oscillatory Activity in Prefrontal Cortex and Hippocampus

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Nucleus accumbens neurochemistry in human anxiety: A 7 T¹H-MRS study