An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors

R. N. Arey, J. F. Enwright, S. M. Spencer, E. Falcon, Angela Ozburn, S. Ghose, C. Tamminga, C. A. Mcclung

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Mice with a mutation in the Clock gene (ClockΔ19) 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 ClockΔ19 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 ClockΔ19 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.

Original languageEnglish (US)
Pages (from-to)342-350
Number of pages9
JournalMolecular Psychiatry
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2014
Externally publishedYes

Fingerprint

Cholecystokinin
Lithium
Ventral Tegmental Area
Genes
Bipolar Disorder
Antimanic Agents
Phenotype
RNA Interference
Histones
Mutation
Brain

Keywords

  • Bipolar disorder
  • Chromatin structure
  • Dopamine
  • Gene expression
  • Lithium

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors. / Arey, R. N.; Enwright, J. F.; Spencer, S. M.; Falcon, E.; Ozburn, Angela; Ghose, S.; Tamminga, C.; Mcclung, C. A.

In: Molecular Psychiatry, Vol. 19, No. 3, 01.03.2014, p. 342-350.

Research output: Contribution to journalArticle

Arey, RN, Enwright, JF, Spencer, SM, Falcon, E, Ozburn, A, Ghose, S, Tamminga, C & Mcclung, CA 2014, 'An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors', Molecular Psychiatry, vol. 19, no. 3, pp. 342-350. https://doi.org/10.1038/mp.2013.12
Arey, R. N. ; Enwright, J. F. ; Spencer, S. M. ; Falcon, E. ; Ozburn, Angela ; Ghose, S. ; Tamminga, C. ; Mcclung, C. A. / An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors. In: Molecular Psychiatry. 2014 ; Vol. 19, No. 3. pp. 342-350.
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