Abstract
Background
Developing novel pharmacological targets beyond monoaminergic systems is now a popular
strategy for finding new ways to treat depression. Salt-inducible kinase (SIK) is
a kinase that regulates the nuclear translocation of cyclic adenosine monophosphate
response element binding protein (CREB)-regulated transcription coactivator (CRTC)
by phosphorylation. Here, we hypothesize that dysfunction of the central SIK-CRTC
system may contribute to the pathogenesis of depression.
Methods
Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models
of depression, various behavioral tests, viral-mediated gene transfer, Western blotting,
coimmunoprecipitation, quantitative real-time reverse transcription polymerase chain
reaction, and immunohistochemistry were used in this study (for in vivo studies, n = 10; for in vitro studies, n = 5).
Results
Both CSDS and CUMS markedly increased the expression of hippocampal SIK2, which reduced
CRTC1 nuclear translocation and binding of CRTC1 and CREB in the hippocampus. Genetic
overexpression of hippocampal SIK2 in naïve mice simulated chronic stress, inducing
depressive-like behaviors in the forced swim test, tail suspension test, sucrose preference
test, and social interaction test, as well as decreasing the brain-derived neurotrophic
factor signaling cascade and neurogenesis in the hippocampus. In contrast, genetic
knockdown and knockout of hippocampal SIK2 protected against CSDS and CUMS, exerting
significant antidepressant-like effects that were mediated via the downstream CRTC1-CREB–brain-derived
neurotrophic factor pathway. Moreover, fluoxetine, venlafaxine, and mirtazapine all
significantly restored the effects of CSDS and CUMS on the hippocampal SIK2-CRTC1
pathway, which was necessary for their antidepressant actions.
Conclusions
The hippocampal SIK2-CRTC1 pathway is involved in the pathogenesis of depression,
and hippocampal SIK2 could be a novel target for the development of antidepressants.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Global burden of disease attributable to mental and substance use disorders: Findings from the Global Burden of Disease Study 2010.Lancet. 2013; 382: 1575-1586
- Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants.Nat Med. 2016; 22: 238-249
- The molecular neurobiology of depression.Nature. 2008; 455: 894-902
- The cellular neurobiology of depression.Nat Med. 2001; 7: 541-547
- The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms.Philos Trans R Soc Lond B Biol Sci. 2012; 367: 2378-2381
- New approaches to antidepressant drug discovery: Beyond monoamines.Nat Rev Neurosci. 2006; 7: 137-151
- Neurobiology of depression.Neuron. 2002; 34: 13-25
- The mesolimbic dopamine reward circuit in depression.Biol Psychiatry. 2006; 59: 1151-1159
- Linking molecules to mood: New insight into the biology of depression.Am J Psychiatry. 2010; 167: 1305-1320
- Stress and depression: Possible links to neuron death in the hippocampus.Bipolar Disord. 2002; 4: 117-128
- Hippocampal volume change in depression: Late- and early-onset illness compared.Br J Psychiatry. 2004; 184: 488-495
- Hippocampal neurogenesis: Regulation by stress and antidepressants.Biol Psychiatry. 2006; 59: 1136-1143
- CREB: A major mediator of neuronal neurotrophin responses.Neuron. 1997; 19: 1031-1047
- CREB: A stimulus-induced transcription factor activated by a diverse array of extracellular signals.Annu Rev Biochem. 1999; 68: 821-861
- Brain-derived neurotrophic factor stimulates the neural differentiation of human umbilical cord blood-derived mesenchymal stem cells and survival of differentiated cells through MAPK/ERK and PI3K/Akt-dependent signaling pathways.J Neurosci Res. 2008; 86: 2168-2178
- BDNF activates CaMKIV and PKA in parallel to block MAG-mediated inhibition of neurite outgrowth.Mol Cell Neurosci. 2008; 38: 110-116
- The role of CREB in depression and antidepressant treatment.Biol Psychiatry. 2006; 59: 1144-1150
- The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity.Dev Neurobiol. 2010; 70: 289-297
- A role for BDNF/TrkB signaling in behavioral and physiological consequences of social defeat stress.Genes Brain Behav. 2011; 10: 424-433
- Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect.Biol Psychiatry. 2001; 49: 753-762
- Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.J Neurosci. 2002; 22: 3251-3261
- Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects.Brain Res. 2005; 1037: 204-208
- Gender differences in the enhanced vulnerability of BDNF+/- mice to mild stress.Int J Neuropsychopharmacol. 2009; 12: 583-588
- Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.Science. 2006; 311: 864-868
- Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents.Curr Neuropharmacol. 2006; 4: 277-291
- BDNF-GSK-3β-β-catenin pathway in the mPFC is involved in antidepressant-like effects of morinda officinalis oligosaccharides in rats.Int J Neuropsychopharmacol. 2017; 20: 83-93
- WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway.Psychopharmacology (Berl). 2015; 232: 1629-1642
- CREB and the CRTC co-activators: Sensors for hormonal and metabolic signals.Nat Rev Mol Cell Biol. 2011; 12: 141-151
- Deregulation of CRTCs in aging and age-related disease risk [published correction appears in Trends Genet 2018 34:326].Trends Genet. 2017; 33: 303-321
- Emerging roles of CREB-regulated transcription coactivatros in brain physiology and pathology.Trends Neurosci. 2017; 40: 720-733
- TORC-SIK cascade regulates CREB activity through the basic leucine zipper domain.FEBS J. 2007; 274: 3202-3209
- Increasing CRTC1 function in the dentate gyrus during memory formation or reactivation increases memory strength without compromising memory quality.J Neurosci. 2012; 32: 17857-17868
- CREB-regulated transcription coactivator 1: Important roles in neurodegenerative disorders.Sheng Li Xue Bao. 2015; 67: 155-162
- Cloning of a novel kinase (SIK) of the SNF1/AMPK family from high salt diet-treated rat adrenal.FEBS Lett. 1999; 453: 135-139
- Regulation of CREB-mediated gene expression by salt inducible kinase.J Steroid Biochem Mol Biol. 2008; 108: 287-291
- Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade.FEBS J. 2006; 273: 2730-2748
- SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB.Neuron. 2011; 69: 106-119
- Salt-inducible kinase is involved in the regulation of corticotropin-releasing hormone transcription in hypothalamic neurons in rats.Endocrinology. 2012; 153: 223-233
- The CRTC1-SIK1 pathway regulates entrainment of the circadian clock.Cell. 2013; 154: 1100-1111
- Cocaine induces the expression of MEF2C transcription factor in rat striatum through activation of SIK1 and phosphorylation of the histone deacetylase HDAC5.Synapse. 2012; 66: 61-70
- Animal research: Reporting in vivo experiments: The ARRIVE guidelines.Br J Pharmacol. 2010; 160: 1577-1579
- Implementing guidelines on reporting research using animals (ARRIVE etc.): New requirements for publication in BJP.Br J Pharmacol. 2015; 172: 3189-3193
- Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signalling pathway.Br J Pharmacol. 2017; 174: 177-194
- Antidepressant-like effects of tetrahydroxystilbene glucoside in mice: Involvement of BDNF signaling cascade in the hippocampus.CNS Neurosci Ther. 2017; 23: 627-636
- Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice.Br J Pharmacol. 2018; 175: 2968-2987
- Tetramethylpyrazine produces antidepressant-like effects in mice through promotion of BDNF signaling pathway.Int J Neuropsychopharmacol. 2015; 18: pyv010
- Hippocampal mTOR signaling is required for the antidepressant effects of paroxetine.Neuropharmacology. 2018; 128: 181-195
- Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus.Br J Pharmacol. 2012; 166: 1872-1887
- Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression.Brain Res Bull. 2017; 134: 211-219
- Gemfibrozil has antidepressant effects in mice: Involvement of the hippocampal brain-derived neurotrophic factor system.J Psychopharmacol. 2018; 32: 469-481
- Chronic mild stress and sucrose consumption: Validity as a model of depression.Physiol Behav. 1996; 60: 1481-1484
- Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.Transl Psychiatry. 2016; 6: E852
- CREB, neurogenesis and depression.Bioessays. 2007; 29: 957-961
- Deletion of CREB-regulated transcription coactivator 1 induces pathological aggression, depression-related behaviors, and neuroplasticity genes dysregulation in mice.Biol Psychiatry. 2012; 72: 528-536
- The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression.Neuropharmacology. 2012; 107: 111-121
- Function and regulation of CREB family transcription factors in the nervous system.Neuron. 2002; 35: 605-623
- The many faces of CREB.Trends Neurosci. 2005; 28: 436-445
- CREB and cAMP response element-mediated gene expression in the ischemic brain.FEBS J. 2007; 274: 3210-3217
- The HPA axis in major depression: Classical theories and new developments.Trends Neurosci. 2008; 31: 464-468
- LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.EMBO J. 2004; 23: 833-843
- The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.Nat Commun. 2014; 5: 4535
- Salt-inducible kinase 2 regulates mitotic progression and transcription in prostate cancer.Mol Cancer Res. 2015; 13: 620-635
- A novel compound ARN-3236 inhibits salt-inducible kinase 2 and sensitizes ovarian cancer cell lines and xenografts to paclitaxel.Clin Cancer Res. 2017; 23: 1945-1954
- Salt-inducible kinases regulate growth through the Hipp signaling pathway in Drosophila.Nat Cell Biol. 2013; 15: 61-71
- Salt-inducible kinase induces cytoplasmic histone deacetylase 4 to promote vascular calcification.EMBO Rep. 2017; 18: 1166-1185
- The protein kinase SIK downregulates the polarity protein Par3.Oncotarget. 2017; 9: 5716-5735
- VEGF as a potential target for therapeutic intervention in depression.Curr Opin Pharmacol. 2008; 8: 14-19
- MTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.Science. 2010; 329: 959-964
- Convergent mechanisms underlying rapid antidepressant action.CNS Drugs. 2018; 32: 197-227
- Brain-derived neurotrophic factor in neurodegenerative diseases.Nat Rev Neurol. 2009; 5: 311-322
- BDNF and schizophrenia: From neurodevelopment to neuronal plasticity, learning, and memory.Front Psychiatry. 2013; 4: 45
- MiRNA-206 and BDNF genes interacted in bipolar I disorder.J Affect Disord. 2014; 162: 116-119
- Transcription-factor-dependent control of adult hippocampal neurogenesis.Cold Spring Harb Perspect Biol. 2015; 7: a018879
- Multiple signal transduction pathways mediated by 5-HT receptors.Mol Neurobiol. 2004; 29: 31-39
- Signaling at G-protein-coupled serotonin receptors: Recent advances and future research directions.Trends Pharmacol Sci. 2008; 29: 454-464
Article info
Publication history
Published online: October 17, 2018
Accepted:
October 4,
2018
Received in revised form:
October 3,
2018
Received:
May 22,
2018
Identification
Copyright
© 2018 Society of Biological Psychiatry.