Cell Type-Specific Loss of SIRT1 in Central Amygdala Leads to Depression-Like Behaviors by Altering Neuronal...

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.

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.

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.

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.