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 journalArticlepeer-review

48 Scopus citations


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
Pages (from-to)336-343
Number of pages8
JournalBiological Psychiatry
Issue number4
StatePublished - 15 Aug 2008
Externally publishedYes


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


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