Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatr. Feb 19, 2021; 11(2): 35-49
Published online Feb 19, 2021. doi: 10.5498/wjp.v11.i2.35
Selective ablation of type 3 adenylyl cyclase in somatostatin-positive interneurons produces anxiety- and depression-like behaviors in mice
Xiao-Yu Yang, Zhao-Liang Ma, Daniel R Storm, Hong Cao, Yu-Qiu Zhang
Xiao-Yu Yang, Zhao-Liang Ma, Hong Cao, Yu-Qiu Zhang, Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institutes of Integrative Medicine, Fudan University, Shanghai 200032, China
Daniel R Storm, Department of Pharmacology, University of Washington, Seattle, WA 98105, United States
Author contributions: Yang XY and Cao H designed and coordinated the study; Yang XY and Ma ZL performed the experiments, acquired, and analyzed data; Storm DR provided the Floxed AC3 mice; Cao H and Zhang YQ interpreted the data; Yang XY, Storm DR and Cao H wrote the manuscript; All authors approved the final version of the article.
Supported by National Natural Science Foundation of China, No. 81771208 and No. 81971043
Institutional animal care and use committee statement: The study was reviewed and approved by the Experimental Animal Ethics Committee of Shanghai Medical College and the Institutional Animal Care & Use Committee (IACUC) of Fudan University (permit No. 20170223-091). All experimental procedures were designed to minimize pain or discomfort to the animals and followed the ethical guidelines of the International Association for the Study of Pain regarding the use of laboratory animal.
Conflict-of-interest statement: All authors have no any conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Hong Cao, MD, PhD, Associate Professor, Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Institutes of Integrative Medicine, Fudan University, Rm 1202 Mingdao Building, No. 131 Dong'an Road, Shanghai 200032, China.
Received: October 13, 2020
Peer-review started: October 13, 2020
First decision: December 4, 2020
Revised: December 9, 2020
Accepted: December 24, 2020
Article in press: December 24, 2020
Published online: February 19, 2021

Major depressive disorder (MDD) is a highly disabling psychiatric syndrome associated with deficits of specific subpopulations of cortical GABAergic interneurons; however, the underlying molecular mechanism remains unknown. Type 3 adenylyl cyclase (ADCY3, AC3), which is important for neuronal excitability, has been implicated in MDD in a genome-wide association study in humans. Moreover, a study reported that ablation of AC3 in mice caused similar symptoms as MDD patients.


To determine if disruption of the AC3 gene in different subtypes of GABAergic interneurons of mice causes depression-like behaviors.


Using immunohistochemistry, we investigated the expression of AC3 in two major subtypes GABAergic interneurons: Somatostatin-positive (SST+) and parvalbumin-positive (PV+) neurons. Genetic manipulations were used to selectively disrupt AC3 expression in SST+ or PV+ interneurons. A series of behavior tests including rotarod test, open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test (TST) were used to evaluate the motor ability, anxiety- and depression- like behaviors, respectively.


Our results indicate that approximately 90.41% of SST+ and 91.22% of PV+ interneurons express AC3. After ablation of AC3 in SST+ interneurons, the mice spent comparable time in the center area in OFT, but significantly less time in the open arms and low frequency of entries to the open arms in EPM. Furthermore, these mice showed prolonged immobility in FST and more freezing in TST. However, there were no significant changes in these behaviors after specific disruption of AC3 in PV+ interneurons.


This study indicates that ablation of AC3 in SST+ interneurons of mice increases anxiety- and depression-like behaviors in mice, supporting the general hypothesis that decreased AC3 activity may play a role in human depression.

Keywords: Type 3 adenylyl cyclase, Somatostatin, Parvalbumin, Anxiety, Depression, Mice

Core Tip: Dysfunction of cortical GABAergic interneurons are thought to contribute to the pathophysiology of stress-related psychiatric disorders. Little is known about the regulation of GABAergic interneurons in depression. Type 3 adenylyl cyclase (AC3) is important for the neuronal excitability and was reported as a top-ranked gene in major depressive disorder (MDD). Here, we found that majority of somatostatin-positive (SST+) and parvalbumin-positive (PV+) GABAergic interneurons express AC3. Selective disruption of AC3 in SST+ but not PV+ interneurons caused anxiety- and depression-like behaviors. Our data suggest that AC3 in specific subtype interneurons played a key role in the etiology of depression, providing new insights for therapeutic interventions for the treatment of MDD.