Abstract
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder worldwide. Several lines of evidence suggest that the dysfunction of somatostatin (SOM) neurons is associated with the pathophysiology of MDD. Importantly, most SOM neurons are γ-aminobutyric acid (GABA) interneurons. However, whether the dysfunction of GABAergic neurotransmission from SOM neurons contributes to the pathophysiology of MDD remains elusive. To address this issue, we investigated the emotional behaviors and relevant molecular mechanism in mice lacking glutamate decarboxylase 67 (GAD67), an isoform of GABA-synthesizing enzyme, specifically in SOM neurons (SOM-GAD67 mice). The SOM-GAD67 mice exhibited anxiety-like behavior in the open-field test without an effect on locomotor activity. The SOM-GAD67 mice showed depression-like behavior in neither the forced swimming test nor the sucrose preference test. In addition, the ability to form contextual fear memory was normal in the SOM-GAD67 mice. Furthermore, the plasma corticosterone level was normal in the SOM-GAD67 mice both under baseline and stress conditions. The expression ratios of p-AktSer473/Akt and p-GSK3βSer9/GSK3β were decreased in the frontal cortex of SOM-GAD67 mice. Taken together, these data suggest that the loss of GAD67 from SOM neurons may lead to the development of anxiety-like but not depression-like states mediated by modification of Akt/GSK3β activities.
Highlights
Major depressive disorder (MDD) affects approximately 10% of the population at some point in their life and is the leading cause of physical impairment, medical comorbidity, and mortality across the world (Penninx et al, 2013; Sato and Yeh, 2013)
The SOM-glutamate decarboxylase 67 (GAD67) mice exhibited significantly less time spent in the center field than the control mice (Figures 1A,C), but the total path length in the open-field test did not differ between the genotypes (Figures 1B,C)
We further evaluated the depression-like state in mice in the forced swimming test and the sucrose preference test
Summary
Major depressive disorder (MDD) affects approximately 10% of the population at some point in their life and is the leading cause of physical impairment, medical comorbidity, and mortality across the world (Penninx et al, 2013; Sato and Yeh, 2013). In the postmortem brain of patients with MDD, the expression levels of SOM were decreased in the dorsolateral prefrontal cortex (Sibille et al, 2011), the subgenual anterior cingulate cortex (Tripp et al, 2011) and the amygdala (Guilloux et al, 2012). Mice subjected to chronic mild stress, an animal model of depression, demonstrated a decrease in the mRNA level of SOM in the prefrontal cortex (Banasr et al, 2017). SOM KO mice displayed no change in emotional behaviors (Zeyda et al, 2001; Viollet et al, 2017) or mild anxiety-like behavior (Lin and Sibille, 2015). Lin and Sibille reported the anxiety-like/depression-like behaviors were pronounced after exposure to chronic mild stress (Lin and Sibille, 2015)
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