Calcium-Sensitive Adenylyl Cyclases in Depression and Anxiety

Behavioral and Biochemical Consequences of Isoform Targeting

Vaishnav Krishnan, Ami Graham, Michelle S. Mazei-Robison, Diane C. Lagace, Kyoung Shim Kim, Shari Birnbaum, Amelia J. Eisch, Pyung Lim Han, Daniel R. Storm, Venetia Zachariou, Eric J. Nestler

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background: Adenylyl cyclases (ACs) represent a diverse family of enzymes responsible for the generation of cyclic adenosine monophosphate (cAMP), a key intracellular second messenger. The Ca2+/calmodulin-stimulated AC1 and AC8 isoforms as well as the calcium-inhibited AC5 isoform are abundantly expressed within limbic regions of the central nervous system. This study examines the contribution of these AC isoforms to emotional behavior. Methods: Male and female AC1/8 double knockout mice (DKO) and AC5 knockout mice (AC5KO) were examined on a series of standard laboratory assays of emotionality. Mice were also assayed for hippocampal cell proliferation and for changes in brain-derived neurotrophic factor signaling in the nucleus accumbens, amygdala, and hippocampus, three forebrain structures involved in the regulation of mood and affect. Results: The AC5KO mice showed striking anxiolytic and antidepressant phenotypes on standard behavioral assays. In contrast, AC1/8 DKO mice were hypoactive, exhibited diminished sucrose preference, and displayed alterations in neurotrophic signaling, generally consistent with a prodepressant phenotype. Neither line of mice displayed alterations in hippocampal cell proliferation. Conclusions: These data illustrate the complex manner in which Ca2+/calmodulin-stimulated ACs contribute to emotional behavior. In addition, they support the possibility that a selective AC5 antagonist would be of therapeutic value against depression and anxiety disorders.

Original languageEnglish (US)
Pages (from-to)336-343
Number of pages8
JournalBiological Psychiatry
Volume64
Issue number4
DOIs
StatePublished - Aug 15 2008

Fingerprint

Adenylyl Cyclases
Knockout Mice
Protein Isoforms
Anxiety
Depression
Calcium
Calmodulin
Cell Proliferation
Phenotype
Brain-Derived Neurotrophic Factor
Anti-Anxiety Agents
Nucleus Accumbens
Second Messenger Systems
Prosencephalon
Amygdala
Anxiety Disorders
Cyclic AMP
Antidepressive Agents
Sucrose
Hippocampus

Keywords

  • AC1
  • AC5
  • AC8
  • calcium-regulated adenylyl cyclases
  • hippocampus
  • knockout mice
  • nucleus accumbens

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Calcium-Sensitive Adenylyl Cyclases in Depression and Anxiety : Behavioral and Biochemical Consequences of Isoform Targeting. / Krishnan, Vaishnav; Graham, Ami; Mazei-Robison, Michelle S.; Lagace, Diane C.; Kim, Kyoung Shim; Birnbaum, Shari; Eisch, Amelia J.; Han, Pyung Lim; Storm, Daniel R.; Zachariou, Venetia; Nestler, Eric J.

In: Biological Psychiatry, Vol. 64, No. 4, 15.08.2008, p. 336-343.

Research output: Contribution to journalArticle

Krishnan, V, Graham, A, Mazei-Robison, MS, Lagace, DC, Kim, KS, Birnbaum, S, Eisch, AJ, Han, PL, Storm, DR, Zachariou, V & Nestler, EJ 2008, 'Calcium-Sensitive Adenylyl Cyclases in Depression and Anxiety: Behavioral and Biochemical Consequences of Isoform Targeting', Biological Psychiatry, vol. 64, no. 4, pp. 336-343. https://doi.org/10.1016/j.biopsych.2008.03.026
Krishnan, Vaishnav ; Graham, Ami ; Mazei-Robison, Michelle S. ; Lagace, Diane C. ; Kim, Kyoung Shim ; Birnbaum, Shari ; Eisch, Amelia J. ; Han, Pyung Lim ; Storm, Daniel R. ; Zachariou, Venetia ; Nestler, Eric J. / Calcium-Sensitive Adenylyl Cyclases in Depression and Anxiety : Behavioral and Biochemical Consequences of Isoform Targeting. In: Biological Psychiatry. 2008 ; Vol. 64, No. 4. pp. 336-343.
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