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
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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.
