Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1–cAMP Response Element Binding–Brain-Derived Neurotrophic Factor Pathway

Jiang, Bo; Wang, Hao; Wang, Jinliang; Wang, Yingjie; Zhu, Qing; Wang, Chengniu; Song, Lu; Gao, Tingting; Wang, Yuan; Meng, Guoliang; Wu, Feng; Ling, Yong; Zhang, Wei; Li, Jun-Xu

doi:10.1016/j.biopsych.2018.10.004

Cited by 59 publications

(58 citation statements)

References 73 publications

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“…[12] Previous research proposed a down-regulation of CREB activity in chronic stress models in rodents. [13] Long-term treatment of fluoxetine enhances cAMP levels, subsequently activates protein kinase A (PKA) and up-regulates CREB mRNA in chronic stress-stimulated hippocampus, cortex and hypothalamus [14]. CREB signaling regulates the expression of genes which promote synapses and neural plasticity, as evidenced by the presence of CREB elements in the BDNF promoter region [15][16][17].…”

Section: Instructionmentioning

confidence: 99%

Anti-depressant effects of oil from fructus gardeniae via PKA-CREB-BDNF signaling

et al. 2019

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The dried ripe fruit of Gardenia jasminoides Ellis was usually applied as an herb medicine in Traditional Chinese Medicine. It was suggested that the Gardenia jasminoides oil extract (oil from Fructus Gardeniae [OFG]) might serve as a potential treatment for depression, whereas its pathogenesis still remained not fully understood. The present research was conducted to evaluate the anti-depressive effect of OFG in mice and explore its potential mechanism. The OFG and ketamine (KET) were intragastrically and intraperitoneally treated, respectively. Thereafter, the animals were subjected to the behavior tests. The expressions of protein kinase A (PKA), brain derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB) in hippocampus were detected by Western blot. The selective PKA inhibitor H-89 was also applied to confirm the mechanism. As a result, OFG and KET treatment improved the behavior performance. Furthermore, the administrations of OFG effectively enhanced the expressions of PKA, p-CREB, and BDNF. With the application of selective PKA inhibitor H-89, the ameliorated effects caused by OFG were blocked, but not by KET. In conclusion, the presented work indicated that OFG-exerted protective effect on depression through PKA-CREB-BDNF signaling.

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Section: Instructionmentioning

confidence: 99%

Anti-depressant effects of oil from fructus gardeniae via PKA-CREB-BDNF signaling

et al. 2019

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“…Salt-inducible kinases (SIKs, SIK1-3) are serine/threonine kinases which belong to the family of AMP-activated protein kinases (AMPKs), and have wide expression in many tissues such as adipocytes, hypothalamus, hippocampus, cerebral cortex and so on ( Wang et al, 1999 ; Feldman et al, 2000 ; Katoh et al, 2004 ; Gallo and Iadecola, 2011 ; Jiang et al, 2019 ). SIKs have so far mainly been suggested to regulate gene expression by phosphorylating transcriptional regulators like the cAMP response element binding protein (CREB)-regulated transcription co-activators (CRTCs) ( Takemori et al, 2007 ; Takemori and Okamoto, 2008 ; Choi et al, 2011 ; Gallo and Iadecola, 2011 ; Jiang et al, 2019 ). CRTCs, when phosphorylated, are sequestered in the cytoplasm where they are unable to activate the CREB-induced gene transcription ( Altarejos and Montminy, 2011 ; Jurek et al, 2015 ; Rahnert et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, CRTCs are dephosphorylated in response to elevations in cAMP, leading to nuclear translocation and binding to CREB ( Altarejos and Montminy, 2011 ; Jurek et al, 2015 ; Rahnert et al, 2016 ). In 2019, we have reported that chronic stress-induced depression was accompanied by increased SIK2 expression and decreased nuclear CRTC1 translocation and CRTC1-CREB binding in the hippocampus ( Jiang et al, 2019 ). Hippocampal SIK2 overexpression mimicked chronic stress that produced depressive-like phenotypes in naïve mice, whereas knockdown and knockout of hippocampal SIK2 protected against chronic stress ( Jiang et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…In 2019, we have reported that chronic stress-induced depression was accompanied by increased SIK2 expression and decreased nuclear CRTC1 translocation and CRTC1-CREB binding in the hippocampus ( Jiang et al, 2019 ). Hippocampal SIK2 overexpression mimicked chronic stress that produced depressive-like phenotypes in naïve mice, whereas knockdown and knockout of hippocampal SIK2 protected against chronic stress ( Jiang et al, 2019 ). Furthermore, the BDNF signaling cascade mediates the role of the hippocampal SIK2-CRTC1 system in the pathogenesis of depression ( Jiang et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway

Liu

Tang

et al. 2021

Front. Pharmacol.

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Depression is a widespread chronic medical illness affecting thoughts, mood, and physical health. However, the limited and delayed therapeutic efficacy of monoaminergic drugs has led to intensive research efforts to develop novel antidepressants. ARN-3236 is the first potent and selective inhibitor of salt-inducible kinase 2 (SIK2). In this study, a multidisciplinary approach was used to explore the antidepressant-like actions of ARN-3236 in mice. Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, high performance liquid chromatography-tandem mass spectrometry, stereotactic infusion, viral-mediated gene transfer, western blotting, co-immunoprecipitation and immunofluorescence were used together. It was found that ARN-3236 could penetrate the blood-brain barrier. Repeated ARN-3236 administration induced significant antidepressant-like effects in both the CSDS and CUMS models of depression, accompanied with fully preventing the stress-enhanced SIK2 expression and cytoplasmic translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) in the hippocampus. ARN-3236 treatment also completely reversed the down-regulating effects of CSDS and CUMS on the hippocampal brain-derived neurotrophic factor (BDNF) system and neurogenesis. Moreover, we demonstrated that the hippocampal CRTC1-CREB-BDNF pathway mediated the antidepressant-like efficacy of ARN-3236. Collectively, ARN-3236 possesses strong protecting effects against chronic stress, and could be a novel antidepressant beyond monoaminergic drugs.

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“…CRTC1 is involved in synaptic plasticity and memory formation [18][19][20] and participates in the regulation of energy and mood balance 21,22 . Importantly, CRTC1 has been implicated in rodent depressive-like behavior 23 , which can be triggered by excessive CRTC1 phosphorylation and cytoplasmic sequestration as a response to chronic stress 24 . Thus, the Crtc1 knock-out (Crtc1 -/-) mouse was shown to be a useful model to study the pathways and mechanisms linking metabolic diseases with depression 21,22,25 and to understand associated resistance to classic antidepressants, in particular to fluoxetine 26,27 .…”

Section: Introductionmentioning

confidence: 99%

Deletion ofCrtc1leads to hippocampal neuroenergetic impairments associated with depressive-like behavior

Cherix

Poitry‐Yamate

Lanz

et al. 2020

Preprint

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Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models, can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying the underlying molecular/physiological origin, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point towards the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1's and MeS's relationship to MD and establishes depression-related markers with clinical potential.

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Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1–cAMP Response Element Binding–Brain-Derived Neurotrophic Factor Pathway

Cited by 59 publications

References 73 publications

Anti-depressant effects of oil from fructus gardeniae via PKA-CREB-BDNF signaling

Anti-depressant effects of oil from fructus gardeniae via PKA-CREB-BDNF signaling

The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway

Deletion ofCrtc1leads to hippocampal neuroenergetic impairments associated with depressive-like behavior

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