- 作者：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
- 关键词：AC1 ; AC5 ; AC8 ; calcium-regulated adenylyl cyclases ; hippocampus ; knockout mice ; nucleus accumbens
- 刊名：Biological Psychiatry
- 出版年：2008
- 出版时间：15 August 2008
- 年：2008
- 卷：64
- 期：4
- 页码：336-343
- 全文大小：1120 K
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.