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 Ca(2+)/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 Ca(2+)/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.
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 Ca(2+)/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 Ca(2+)/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.
Authors: Vaishnav Krishnan; Ming-Hu Han; Danielle L Graham; Olivier Berton; William Renthal; Scott J Russo; Quincey Laplant; Ami Graham; Michael Lutter; Diane C Lagace; Subroto Ghose; Robin Reister; Paul Tannous; Thomas A Green; Rachael L Neve; Sumana Chakravarty; Arvind Kumar; Amelia J Eisch; David W Self; Francis S Lee; Carol A Tamminga; Donald C Cooper; Howard K Gershenfeld; Eric J Nestler Journal: Cell Date: 2007-10-19 Impact factor: 41.582
Authors: A C Conti; J W Maas; L M Muglia; B A Dave; S K Vogt; T T Tran; E J Rayhel; L J Muglia Journal: Neuroscience Date: 2007-02-28 Impact factor: 3.590
Authors: Feng Wei; Chang Shen Qiu; Susan J Kim; Lisa Muglia; James W Maas; Victor V Pineda; Hai Ming Xu; Zhou Feng Chen; Daniel R Storm; Louis J Muglia; Min Zhuo Journal: Neuron Date: 2002-11-14 Impact factor: 17.173
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Authors: Richard L Hauger; Victoria Risbrough; Robert H Oakley; J Alberto Olivares-Reyes; Frank M Dautzenberg Journal: Ann N Y Acad Sci Date: 2009-10 Impact factor: 5.691