Cell Type‐Specific Loss of SIRT1 in Central Amygdala Leads to Depression‐Like Behaviors by Altering Neuronal Excitability in Mice

ABSTRACT Aim The current understanding of the underlying pathogenesis of depression is still limited. Silent information regulator 1 (SIRT1) has been shown to mediate the development of depression. However, the underlying mechanisms are not well understood. Methods SIRT1 flox/flox mice were used to observe the effect of selective knockdown of SIRT1 in glutamatergic or GABAergic neurons of the central amygdala (CeA) on depression‐like behaviors. Western blot and immunofluorescence staining were used to determine the protein levels. Optogenetic technology was used to manipulate neuronal excitability. Whole cell patch‐clamp recordings and c‐Fos immunofluorescence staining were used to detect the excitability of different types of neurons. Results Our study demonstrated that selective knockdown of SIRT1 in CeA glutamatergic neurons induced depression‐like behaviors and increased the excitability of glutamatergic neurons in mice. Optogenetic inhibition of glutamatergic neurons in CeA significantly ameliorated the depression‐like behaviors induced by downregulation of SIRT1 in CeA glutamatergic neurons. In addition, selective knockdown of SIRT1 in CeA GABAergic neurons could also induce depression‐like behaviors, accompanied by decreased excitability of GABAergic neurons and increased excitability of glutamatergic neurons. Optogenetic activation of GABAergic neurons in CeA significantly alleviated the depression‐like behaviors induced by downregulation of SIRT1 in CeA GABAergic neurons. Conclusion Our findings indicate that cell‐type‐specific loss of SIRT1 may mediate the development of depression‐like behaviors in mice by divergent changes in the excitability of CeA glutamatergic and GABAergic neurons. These data demonstrate a new mechanism for the development of depression and provide a potential therapeutic target for depression.