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Calcium-Sensitive Adenylyl Cyclases in Depression and Anxiety: Behavioral and Biochemical Consequences of Isoform Targeting
- Calcium-Sensitive Adenylyl Cyclases in Depression and Anxiety: Behavioral and Biochemical Consequences of Isoform Targeting
- Krishnan V.; Graham A.; Mazei-Robison M.S.; Lagace D.C.; Kim K.-S.; Birnbaum S.; Eisch A.J.; Han P.-L.; Storm D.R.; Zachariou V.; Nestler E.J.
- Ewha Authors
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- Biological Psychiatry
- Biological Psychiatry vol. 64, no. 4, pp. 336 - 343
- SCI; SCIE; SCOPUS
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- 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. © 2008 Society of Biological Psychiatry.
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