Abstract
Background
Deficiency in neuronal structural plasticity is involved in the development of major
depressive disorder. TWIST1, a helix-loop-helix transcription factor that is essential
for morphogenesis and organogenesis, is normally expressed at low levels in mature
neurons. However, it is poorly understood what role TWIST1 plays in the brain and
whether it is involved in the pathophysiology of depression.
Methods
Depressive-like behaviors in C57BL/6J mice were developed by chronic social defeat
stress. Genetic and pharmacological approaches were used to investigate the role of
the TWIST1–miR-214–PPAR-δ signaling pathway in depressive-like behaviors. Molecular
biological and morphological studies were performed to define the molecular mechanisms
downstream of TWIST1.
Results
The expression of TWIST1 was positively correlated with depressive behaviors in humans
and mice. Chronic stress elevated TWIST1 expression in the medial prefrontal cortex
of mice, which was reversed by fluoxetine treatment. While the overexpression of TWIST1
increased susceptibility to stress, the knockdown of TWIST1 prevented the defective
morphogenesis of dendrites of pyramidal neurons in layer II/III of the medial prefrontal
cortex and alleviated depressive-like behaviors. Mechanistically, this prodepressant
property of TWIST1 was mediated, at least in part, through the repression of miR-214–PPAR-δ
signaling and mitochondrial function, which was also mimicked by genetic and pharmacological
inhibition of PPAR-δ.
Conclusions
These results suggest that TWIST1 in the medial prefrontal cortex mediates chronic
stress–induced dendritic remodeling and facilitates the occurrence of depressive-like
behavior, providing new information for developing drug targets for depression therapy.
Keywords
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Article info
Publication history
Published online: September 10, 2020
Accepted:
September 1,
2020
Received in revised form:
August 20,
2020
Received:
December 14,
2019
Identification
Copyright
© 2020 Society of Biological Psychiatry.
