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An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors
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An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors
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Journal Article
An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors
2014
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adult and adolescent clinical studies
/ Analysis
/ Animals
/ Anxiety
/ Behavior
/ Behavior, Animal - physiology
/ Biological and medical sciences
/ Bipolar Disorder - drug therapy
/ Bipolar Disorder - metabolism
/ Bipolar Disorder - physiopathology
/ Cholecystokinin - biosynthesis
/ Cholecystokinin - physiology
/ Dopamine
/ Genes
/ Histone-Lysine N-Methyltransferase - metabolism
/ Humans
/ Lithium
/ Lithium Chloride - pharmacology
/ Lithium Chloride - therapeutic use
/ Male
/ Mania
/ Medicine
/ Mice
/ Mutation
/ Myeloid-Lymphoid Leukemia Protein - metabolism
/ Pharmacology. Drug treatments
/ Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
/ Psychology. Psychoanalysis. Psychiatry
/ Ventral Tegmental Area - drug effects
