An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors
Mice with a mutation in the Clock gene ( Clock Δ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium’s effectiveness on these mice remain unclear. Here, we find that cholecystokinin ( Cck ) is...
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Published in | Molecular psychiatry Vol. 19; no. 3; pp. 342 - 350 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.03.2014
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Mice with a mutation in the
Clock
gene (
Clock
Δ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium’s effectiveness on these mice remain unclear. Here, we find that
cholecystokinin
(
Cck
) is a direct transcriptional target of CLOCK and levels of
Cck
are reduced in the ventral tegmental area (VTA) of
Clock
Δ19 mice. Selective knockdown of
Cck
expression
via
RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores
Cck
expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in
Cck
expression in the
Clock
Δ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in
Cck
expression in the VTA with mood stabilizer treatment. These studies identify a key role for
Cck
in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
ISSN: | 1359-4184 1476-5578 |
DOI: | 10.1038/mp.2013.12 |