Loss of Glutamate Decarboxylase 67 in Somatostatin-Expressing Neurons Leads to Anxiety-Like Behavior and Alteration in the Akt/GSK3β Signaling Pathway

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.