Abstract
Previous genomic studies in humans indicate that SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, is involved in anxiety and depression, but the mechanisms are unclear. We previously showed that SIRT1 is highly activated in the nuclear fraction of the dentate gyrus of the chronically stressed animals and inhibits memory formation and increases anhedonic behavior during chronic stress, but specific functional targets of cytoplasmic SIRT1 are unknown. Here, we demonstrate that SIRT1 activity rapidly modulates intrinsic and synaptic properties of the dentate gyrus granule cells and anxiety behaviors through deacetylation of BK channel α subunits in control animals. Chronic stress decreases BKα channel membrane expression, and SIRT1 activity has no rapid effects on synaptic transmission or intrinsic properties in the chronically stressed animal. These results suggest SIRT1 activity rapidly modulates the physiological function of the dentate gyrus, and this modulation participates in the maladaptive stress response.
Highlights
Previous genomic studies in humans indicate that SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, is involved in anxiety and depression, but the mechanisms are unclear
Our results showed that the acetylation level of p53 was modulated by 50 μΜ SIRT1 activator and 1 μΜ SIRT1 inhibitor IV bath application, indicating the validation of the activation and inhibition effects of these chemicals
In this study, we demonstrated that SIRT1 activity rapidly modulated glutamatergic synaptic transmission and intrinsic properties in dentate gyrus granule cells of the hippocampus
Summary
Previous genomic studies in humans indicate that SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, is involved in anxiety and depression, but the mechanisms are unclear. We demonstrate that SIRT1 activity rapidly modulates intrinsic and synaptic properties of the dentate gyrus granule cells and anxiety behaviors through deacetylation of BK channel α subunits in control animals. Chronic stress decreases BKα channel membrane expression, and SIRT1 activity has no rapid effects on synaptic transmission or intrinsic properties in the chronically stressed animal. These results suggest SIRT1 activity rapidly modulates the physiological function of the dentate gyrus, and this modulation participates in the maladaptive stress response. No effect of SIRT1 activity was observed in animals previously exposed to CVS, and chronic stress decreased BK channel membrane expression levels This mechanism may underlie the stress-induced impairment of SIRT1 rapid effect. We show that modulation of SIRT1 activity in the dentate gyrus can rapidly affect anxiety behavior in a BK channel-dependent manner
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