title: Ablation of Type III Adenylyl Cyclase in Mice Causes Reduced Neuronal Activity, Altered Sleep Pattern, and Depression-like Phenotypes.
abstract: Although major depressive disorder (MDD) has low heritability, a genome-wide association study in humans has recently implicated type 3 adenylyl cyclase (AC3; ADCY3) in MDD. Moreover, the expression level of AC3 in blood has been considered as a MDD biomarker in humans. Nevertheless, there is a lack of supporting evidence from animal studies.
  
  
  
  We employed multiple approaches to experimentally evaluate if AC3 is a contributing factor for major depression using mouse models lacking the Adcy3 gene.
  
  
  
  We found that conventional AC3 knockout (KO) mice exhibited phenotypes associated with MDD in behavioral assays. Electroencephalography/electromyography recordings indicated that AC3 KO mice have altered sleep patterns characterized by increased percentage of rapid eye movement sleep. AC3 KO mice also exhibit neuronal atrophy. Furthermore, synaptic activity at cornu ammonis 3-cornu ammonis 1 synapses was significantly lower in AC3 KO mice, and they also exhibited attenuated long-term potentiation as well as deficits in spatial navigation. To confirm that these defects are not secondary responses to anosmia or developmental defects, we generated a conditional AC3 floxed mouse strain. This enabled us to inactivate AC3 function selectively in the forebrain and to inducibly ablate it in adult mice. Both AC3 forebrain-specific and AC3 inducible knockout mice exhibited prodepression phenotypes without anosmia.
  
  
  
  This study demonstrates that loss of AC3 in mice leads to decreased neuronal activity, altered sleep pattern, and depression-like behaviors, providing strong evidence supporting AC3 as a contributing factor for MDD.
authors: Department of Pharmacology, University of Washington, Seattle, Washington; Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire. Electronic address: chenx8@u.washington.edu.
authors: Xuanmao
authors: X
authors: Chen
authors: Department of Pharmacology, University of Washington, Seattle, Washington.
authors: Jie
authors: J
authors: Luo
authors: Department of Pharmacology, University of Washington, Seattle, Washington.
authors: Yihua
authors: Y
authors: Leng
authors: Department of Pharmacology, University of Washington, Seattle, Washington.
authors: Yimei
authors: Y
authors: Yang
authors: Department of Pharmacology, University of Washington, Seattle, Washington; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington.
authors: Larry S
authors: LS
authors: Zweifel
authors: Howard Hughes Medical Institute, Department of Biochemistry, School of Medicine, University of Washington, Seattle, Washington.
authors: Richard D
authors: RD
authors: Palmiter
authors: Department of Pharmacology, University of Washington, Seattle, Washington.
authors: Daniel R
authors: DR
authors: Storm
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003865:Major Depressive Disorder / Q000201:enzymology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012893:Sleep Wake Disorders / Q000503:physiopathology; D065854:Spatial Navigation / Q000502:physiology
chemical_list: D000262:Adenylyl Cyclases; C421784:adenylate cyclase 3
keywords: ADCY3); Ciliopathies; Major depressive disorder (MDD); Neuronal activity; Primary cilia; Sleep alteration; Type III adenylyl cyclase (AC3