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

50 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

Bibliographical note

Funding Information:
This work was supported by grants from the National Institute on Drug Abuse (AJE), the Canadian Institutes of Health Research (DCL), and the National Institute of Mental Health (EJN). We would like to thank Megumi Adachi and Cathy Steffen for excellent technical assistance.


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


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